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Serpin (serine protease inhibitor)
Figure 1: Recent serpin structures: the structure of the serpin protein Z-dependent inhibitor (PZI - in green/magenta) in complex with protein Z (cyan/red). Protein Z itself is a catalytically inactive serine protease that functions in this instance as a co-factor. The PZI / Protein Z complex is a highly effective inhibitor of the coagulation protease factor Xa.[1]
Identifiers
SymbolSerpin
PfamPF00079
InterProIPR000215
PROSITEPDOC00256
SCOP21hle / SCOPe / SUPFAM
CDDcd00172
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1m37A:1-378 1hleB:349-379 1jrrA:1-415

1by7A:1-415 1ovaA:1-385 1uhgA:1-385 1jtiB:1-385 1attB:77-433 1nq9L:76-461 1oyhI:76-461 1e03L:76-461 1e05I:76-461 1br8L:76-461 1r1lL:76-461 1lk6L:76-461 1antL:76-461 2behL:76-461 1dzhL:76-461 1athA:78-461 1tb6I:76-461 2antI:76-461 1dzgI:76-461 1azxL:76-461 1jvqI:76-461 1sr5A:76-461 1e04I:76-461 1xqgA:1-375 1xu8B:1-375 1wz9B:1-375 1xqjA:1-375 1c8oA:1-300 1m93A:1-55 1f0cA:1-305 1k9oI:18-392 1sek :18-369 1atu :45-415 1ezxB:383-415 8apiA:43-382 1qmbA:49-376 1iz2A:43-415 1oo8A:43-415 1d5sB:378-415 7apiA:44-382 1qlpA:43-415 1ophA:43-415 1kct :44-415 2d26A:43-382 9apiB:383-415 1psi :47-415 1hp7A:43-415 3caaA:50-383 1qmnA:43-420 4caaB:390-420 2achA:47-383 1as4A:48-383 1yxaB:42-417 1lq8F:376-406 2paiB:374-406 1paiB:374-406 1jmoA:119-496 1jmjA:119-496 1oc0A:25-402 1dvnA:25-402 1b3kD:25-402 1dvmD:25-402 1a7cA:25-402 1c5gA:25-402 1db2B:26-402 9paiA:25-402 1lj5A:25-402 1m6qA:138-498 1jjoD:101-361

1imvA:49-415

Serpins are a group of proteins with similar structures that were first identified as a set of proteins able to inhibit proteases. The acronym serpin was originally coined because many serpins inhibit chymotrypsin-like serine proteases (serine protease inhibitors).[2][3][4]

The first members of the serpin superfamily to be extensively studied were the human plasma proteins antithrombin and antitrypsin, which play key roles in controlling blood coagulation (e.g. Figure 1) and inflammation, respectively. Initially, research focused upon their role in human disease: antithrombin deficiency results in thrombosis and antitrypsin deficiency causes emphysema. In 1980 Hunt and Dayhoff made the surprising discovery that both these molecules share significant amino acid sequence similarity to the major protein in chicken egg white, ovalbumin, and they proposed a new protein superfamily.[5] Over 1000 serpins have now been identified, these include 36 human proteins, as well as molecules in plants, fungi, bacteria, archaea and certain viruses.[6][7][8] Serpins are thus the largest and most diverse family of protease inhibitors.[9]

While most serpins control proteolytic cascades, certain serpins do not inhibit enzymes, but instead perform diverse functions such as storage (ovalbumin, in egg white), hormone carriage proteins (thyroxine-binding globulin, cortisol-binding globulin) and molecular chaperones (HSP47). The term serpin is used to describe these latter members as well, despite their noninhibitory function.[10]

As serpins control processes such as coagulation and inflammation, these proteins are the target of medical research. However, serpins are also of particular interest to the structural biology and protein folding communities, because they undergo a unique and dramatic change in shape (or conformational change) when they inhibit target proteases.[11] This is unusual — most classical protease inhibitors function as simple "lock and key" molecules that bind to and block access to the protease active site (see, for example, bovine pancreatic trypsin inhibitor). While the serpin mechanism of protease inhibition confers certain advantages, it also has drawbacks, and serpins are vulnerable to mutations that result in protein misfolding and the formation of inactive long-chain polymers (serpinopathies).[12][13][14] Serpin polymerisation reduces the amount of active inhibitor, as well as accumulation of serpin polymers, causing cell death and organ failure. For example, the serpin antitrypsin is primarily produced in the liver, and antitrypsin polymerisation causes liver cirrhosis.[14] Understanding serpinopathies also provides insights on protein misfolding in general, a process common to many human diseases, such as Alzheimer's and Creutzfeldt-Jakob disease.[13]

Cross-class inhibitors

Figure 2: The X-ray crystal structure of the archetypal serine protease chymotrypsin (pdb code 4CHA).[15] The three catalytic residues (His 57, Asp 102 and Ser 195) are labeled.

Most inhibitory serpins target chymotrypsin-like serine proteases (see Table 1 and Figure 2). These enzymes are defined by the presence of a nucleophilic serine residue in their catalytic site. Examples include thrombin, trypsin, and human neutrophil elastase.[16]

Some serpins inhibit other classes of protease and are termed "cross-class inhibitors". A number of such serpins have been shown to target cysteine proteases. These enzymes differ from serine proteases in that they are defined by the presence of a nucleophilic cysteine residue, rather than a serine residue, in their catalytic site.[17] Nonetheless, the enzymatic chemistry is similar, and serpins most likely inhibit both classes of enzyme in a similar fashion.[18]

Examples of cross-class inhibitory serpins include squamous cell carcinoma antigen 1 (SCCA-1) and the avian serpin myeloid and erythroid nuclear termination stage-specific protein (MENT) both inhibit papain-like cysteine proteases[19][20][21]

The viral serpin crmA is a suppressor of the inflammatory response through inhibition of IL-1 and IL-18 processing by the cysteine protease caspase-1.[22] In eukaryotes, a plant serpin has been shown to inhibit metacaspases[23] and a papain-like cysteine protease.[24] It is presently unclear whether any mammalian serpins function to inhibit caspases in vivo.

Localization and roles

Figure 3: The hormone cortisol bound to the serpin corticosteroid-binding globulin.[25]

Approximately two-thirds of human serpins perform extracellular roles. For example, extracellular serpins regulate the proteolytic cascades central to blood clotting (antithrombin), the inflammatory response (antitrypsin, antichymotrypsin, and C1 inhibitor) and tissue remodeling (PAI-1). Non-inhibitory extracellular serpins also perform important roles. Thyroxine-binding globulin and cortisol-binding globulin transport the hormones thyroxine and cortisol, respectively (Figure 3).[25][26] The protease renin cleaves off a ten-amino acid N-terminal peptide from angiotensinogen to produce the peptide hormone angiotensin I.[27] Table 1 provides a brief summary of human serpin function, as well as some of the diseases that result from serpin deficiency.

The first Intracellular members of the serpin superfamily were identified in the early 1990s.[28][29] As all nine serpins in Caenorhabditis elegans lack signal sequences, they are probably intracellular.[30] Based upon these data it seems likely that the ancestral serpin to human serpins was an intracellular molecule.

The protease targets of intracellular inhibitory serpins have been more difficult to identify. Characterization is complicated by the observation that many of these molecules appear to perform overlapping roles. Further many human serpins lack precise functional equivalents in model organisms such as the mouse. An important function of intracellular serpins may be to protect against the inappropriate activity of proteases inside the cell.[31] For example, one of the best-characterised human intracellular serpins is SERPINB9, which inhibits the cytotoxic granule protease granzyme B. In doing so, SERPINB9 may protect against inadvertent release of granzyme B and premature or unwanted activation of cell death pathways.[32]

Intracellular serpins also perform roles distinct from protease inhibition. For example, the avian nuclear cysteine protease inhibitor MENT, acts as a chromatin remodelling molecule in avian red blood cells.[20][33]

Phylogenetic studies show that most intracellular serpins belong to a single clade (see Table 1). Exceptions include the non-inhibitory heat shock serpin HSP47, which is a chaperone essential for proper folding of collagen, and cycles between the cis-Golgi and the endoplasmic reticulum.[34]

Structure

Figure 4a: The X-ray crystal structure of native human antitrypsin (pdb code 1QLP).[35] The five-stranded A-sheet is in red, the six-stranded B-sheet in green, and the four-stranded C-sheet in yellow. α-helices are shown in cyan. The RCL is at the top of the molecule in magenta. Two functionally important regions of the serpin, the breach and the shutter, are labelled. The figure was produced using PYMOL Figure 4b: The structure of native murine antichymotrypsin (pdb code 1YXA).[36] Colouring is as for figure 4a. Note that two amino acids of the RCL are partially inserted into the top of the A β-sheet (in red).

Structural biology has played a central role in the understanding of serpin function and biology. Over eighty serpin structures, in a variety of different conformations (described below), have been determined to date. Although the function of serpins varies widely, these molecules all share a common structure (or fold).

The structure of the non-inhibitory serpin ovalbumin, and the inhibitory serpin antitrypsin, revealed the archetype native serpin fold.[37][38] All typically have three β-sheets (termed A, B and C) and eight or nine α-helices (hA-hI) (see figure 4). Serpins also possess an exposed region termed the reactive centre loop (RCL) that, in inhibitory molecules, includes the specificity determining region and forms the initial interaction with the target protease. In antitrypsin, the RCL is held at the top of the molecule and is not pre-inserted into the A β-sheet (figure 4, left panel). This conformation commonly exists in dynamic equilibrium with a partially inserted native conformation[39] seen in other inhibitory serpins (see figure 4, right panel).

Conformational change and inhibitory mechanism

Early studies on serpins revealed that the mechanism by which these molecules inhibit target proteases appeared distinct from the lock-and-key-type mechanism utilised by small protease inhibitors such as the Kunitz-type inhibitors (e.g. basic pancreatic trypsin inhibitor). Indeed, serpins form covalent complexes with target proteases.[40] Structural studies on serpins also revealed that inhibitory members of the family undergo an unusual conformational change, termed the Stressed to Relaxed (S to R) transition.[37][39][41][42] During this structural transition the RCL inserts into β-sheet A (in red in figure 4 and 5) and forms an extra (fourth) β-strand. The serpin conformational change is key to the mechanism of inhibition of target proteases.

When attacking a substrate, serine proteases catalyze peptide bond cleavage in a two-step process. Initially, the catalytic serine performs a nucleophilic attack on the peptide bond of the substrate (Figure 5). This releases the new N-terminus and forms an ester-bond between the enzyme and the substrate. This covalent enzyme-substrate complex is called an acyl enzyme intermediate. Subsequent to this, this ester bond is hydrolysed and the new C-terminus is released. The RCL of a serpin acts as a substrate for its cognate protease. However, after the RCL is cleaved, but prior to hydrolysis of the acyl-enzyme intermediate, the serpin rapidly undergoes the S-to-R transition. Since the RCL is still covalently attached to the protease via the ester bond, the S-to-R transition causes the protease to be moved from the top to the bottom of the serpin. At the same time, the protease is distorted into a conformation, where the acyl enzyme intermediate is hydrolysed extremely slowly.[11] The protease thus remains covalently attached to the target protease and is thereby inhibited. Further, since the serpin has to be cleaved to inhibit the target protases, inhibition consumes the serpin as well. Serpins are therefore irreversible enzyme inhibitors. The serpin mechanism of inhibition is illustrated in figures 5 and 6, and several movies illustrating the serpin mechanism can be viewed at this link.

Mechanism of protease inhibition by serpins
Figure 5:
Left: Structure of the non-covalent complex between insect Serpin1K and inactive rat trypsin (pdb code 1K9O).[43] To trap the encounter complex the trypsin (orange) was mutated to an inactive form unable to cleave the RCL. Serpin colouring is as for figure 4.
Right: Final complex between antitrypsin and active trypsin (pdb code 1EZX).[11] The figure was produced using PYMOL.
Figure 6: Catalytic mechanism of serine proteases (adapted from Serine protease mechanism) illustrating the stage in the cycle that is trapped by serpin inhibitors (magenta circle). The ester bond in the acyl enzyme intermediate is highlighted in red.

Conformational modulation of serpin activity

The conformational mobility of serpins provides a key advantage over static lock-and-key protease inhibitors. In particular, the function of inhibitory serpins can be readily controlled by specific cofactors. The X-ray crystal structures of antithrombin, heparin cofactor II, MENT and murine antichymotrypsin reveal that these serpins adopt a conformation wherein the first two amino acids of the RCL are inserted into the top of the A β-sheet (see figures 4 and 7). The partially inserted conformation is important because co-factors are able to conformationally switch certain partially inserted serpins into a fully expelled form.[44][45] This conformational rearrangement makes the serpin a more effective inhibitor.

The archetypal example of this situation is antithrombin, which circulates in plasma in a partially inserted relatively inactive state. The primary specificity determining residue (the P1 Arginine) points toward the body of the serpin and is unavailable to the protease (Figure 7). Upon binding a high-affinity heparin pentasaccharide sequence within long-chain heparin, antithrombin undergoes a conformational change, RCL expulsion, and exposure of the P1 Arginine. The heparin pentasaccharide-bound form of antithrombin is, thus, a more effective inhibitor of thrombin and factor Xa (figure 7).[46][47] Furthermore, both of these coagulation proteases contain binding sites (called exosites) for heparin. Heparin, therefore, also acts as a template for binding of both protease and serpin, further dramatically accelerating the interaction between the two parties (Figure 7). After the initial interaction, the final serpin complex is formed and the heparin moiety is released. This interaction is physiologically important. For example, after injury to the blood vessel wall, heparin is exposed, and antithrombin is activated to control the clotting response. The understanding of the molecular basis of this interaction formed the basis of the development of Fondaparinux, a synthetic form of Heparin pentasaccharide used as an anti-clotting drug.[48]

Figure 7:
From left to right.
1. The partially inserted conformation of native antithrombin. The P1 Arginine is in purple spheres (from pdb 2ANT).
2. Binding of the high affinity heparin pentasaccharide sequence (in cyan spheres) within long chain heparin (in yellow spheres) (from pdb 1TB6).
Note how the P1 Arginine residue has flipped to a more exposed position.
3. Initial interaction of thrombin (orange) with the RCL. Thrombin also contains a binding site for heparin (from pdb 1TB6).
4. Following docking, the final serpin enzyme complex is formed (illustrated using the antitrypsin / trypsin complex) and heparin is released (from pdb 1EZX).

Certain serpins spontaneously undergo the S-to-R transition as part of their function, to form a conformation termed the latent state (Figure 8). In latent serpins, the first strand of the C-sheet has to peel off to allow full RCL insertion. Latent serpins are unable to interact with proteases and are not protease inhibitors. The transition to latency represents a control mechanism for the serpin PAI-1. PAI-1 is released in the inhibitory conformation, however, undergoes conformational change to the latent state unless it is bound to the cofactor vitronectin.[49] Thus PAI-1 contains an "auto-inactivation" mechanism. Similarly, antithrombin can also spontaneously convert to the latent state as part of its normal function. Finally, the N-terminus of tengpin (see pdbs 2PEE and 2PEF), a serpin from Thermoanaerobacter tengcongensis, is required to lock the molecule in the native inhibitory state. Disruption of interactions made by the N-terminal region results in spontaneous conformational change of this serpin to the latent conformation.[50][51]

Figure 8a: X-ray crystal structure of native PAI-1 (from pdb 1DVM) (stabilised though mutation). The RCL is in magenta, and the first β-strand of the C-β-sheet in yellow. In the absence of vitronectin, PAI-1 converts to the latent form (right) (from pdb 1LJ5). The first strand of the C-sheet has peeled off to allow full RCL insertion.
Figure 8b: Structure of native PAI-1 bound to vitronectin (in cyan) (from pdb 1OCO). Part of the RCL is disordered in this structure and is represented by a dashed line.

Serpin receptor interactions

In humans, extracellular serpin-enzyme complexes are rapidly cleared from circulation. In mammals, one mechanism by which this occurs is via the low-density lipoprotein receptor-related protein (LRP receptor), which binds to inhibitory complexes made by antithrombin, PA1-1, and neuroserpin, causing uptake and subsequent signaling events.[52][53] Thus, as a consequence of the conformational change during serpin-enzyme complex formation, serpins may act as signaling molecules that alert cells to the presence of protease activity.[52] The fate of intracellular serpin-enzyme complexes remains to be characterised.

Recently, it has been shown that the Drosophila serpin necrotic is taken up via the Lipophorin Receptor-1 (LpR1), which is related to the mammalian LDL receptor family. Trafficking studies reveal that following uptake by LpR1, necrotic is delivered to lysosomes where it is targeted for degradation.[54]

Conformational change and non-inhibitory function

Certain non-inhibitory serpins also use the serpin conformational change as part of their function. For example, the native (S) form of thyroxine-binding globulin has high affinity for thyroxine, whereas the cleaved (R) form has low affinity. In similar manner, native (S) Cortisol-Binding Globulin (CBG) has higher affinity for cortisol than its cleaved (R) counterpart (Figure 3). Thus, in these serpins, RCL cleavage and the S to R transition has been commandeered to allow for ligand release, rather than protease inhibition.[25][26][55]

Serpins, serpinopathies and human disease

Figure 9: Model illustrating the ideas behind the proposed A-sheet mechanism of serpin polymerisation.[14][56] The A β-sheet is in red. The RCL (magenta) of the orange molecule is inserted into the bottom of the A-sheet of the white molecule.

Serpins are vulnerable to inactivating disease-causing mutations that result in the formation of misfolded polymers or protein aggregates ("serpinopathies"). Well-characterised serpinopathies include alpha 1-antitrypsin deficiency (alpha-1), which may cause familial emphysema and sometimes liver cirrhosis, certain familial forms of thrombosis related to antithrombin deficiency, types 1 and 2 hereditary angioedema (HAE) related to deficiency of C1-inhibitor, and familial encephalopathy with neuroserpin inclusion bodies (FENIB; a rare type of dementia caused by neuroserpin polymerisation).[13][14] Serpins thus belong to a large group of molecules such as the prion proteins and the glutamine repeat containing proteins that cause proteopathies or conformational diseases.[13]

Serpin polymerisation causes disease in two ways. First, the lack of active serpin results in uncontrolled protease activity and tissue destruction; this is seen in the case of antitrypsin deficiency. Second, the polymers themselves clog up the endoplasmic reticulum of cells that synthesize serpins, eventually resulting in cell death and tissue damage. In the case of antitrypsin deficiency, antitrypsin polymers cause the death of liver cells, sometimes resulting in liver damage and cirrhosis. Within the cell, serpin polymers are removed via endoplasmic reticulum associated degradation.[57] However, the mechanism by which serpin polymers cause cell death remains to be fully understood.

Like cleaved serpins, serpin polymers are hyperstable with respect to heating, and each serpin monomer appears to have undergone the stressed to relaxed transition. Furthermore, serpin polymers are unable to inhibit target proteases, suggesting that the RCL is unavailable and inserted into the A-sheet. In the absence of definitive structural data, it was, therefore, postulated that serpins polymerise via a mechanism known as A-sheet polymerisation.[14] In normal function the RCL inserts into the A β-sheet to form a fourth strand (figure 4). In the A-sheet polymerisation model, it was suggested that the RCL of one serpin molecule spontaneously inserted into the A-sheet of another, to form a long-chain polymer (figure 9). In effect, it was, thus, proposed that polymerization occurred as a consequence of the requirement of the serpin scaffold to accept an additional β-strand.

Serpins were one of the first families for which disease-causing mutations were directly analyzed in reference to the available crystal structures.[58] In support of the A-sheet polymerisation model, it was noted that many serpin mutations that cause polymerisation localise to two distinct regions of the molecule (highlighted in figure 4a) termed the shutter and the breach. The shutter and the breach contain highly conserved residues, underlie the path of RCL insertion, and are proposed to be important for conformational change.

Two structures of cleaved serpin polymers have been solved; both of which reveal RCL / A-sheet sheet linkages similar to those predicted by the A sheet polymerisation mechanism.[59][60] However, in direct contrast to the known properties of physiological serpin polymers, crystals of cleaved serpin A-sheet polymers readily dissociate into monomeric forms.[59][60]

Figure 10: The structure of a domain swapped antithrombin dimer reveals one mechanism via which serpins can polymerise (pdb code 2ZNH).[12]

A large body of data now suggest that the events associated with serpin polymerisation occur during the folding of the molecule, and that mutations that cause serpinopathies interfere with the ability of the serpin to fold to the metastable native state.[61] In normal serpin folding, the serpin rapidly moves through a key folding intermediate to attain the native state. Many studies have shown that it is the serpin folding intermediate that has the ability to polymerise, hence it is important that this folding species rapidly moves on to adopt native state. It was shown that mutations such as the Z-antitrypsin variant (Glu 342 to Lys) somehow prevented the final stage of seprin folding and caused the accumulation of the folding intermediate. As a result, population of the folding intermediate resulted in polymer formation.[61] It was noted that once folded, the Z-antitrypsin variant closely resembles wild-type material in terms of thermal stability and inhibitory activity.[61][62]

Together, these data have presented an important challenge to the A-sheet model for serpin polymerisation. On the one hand, the idea that serpin polymer formation essentially takes advantage of the serpin mechanism of conformational change is an attractive one. On the other, the biophyiscal data in particular suggest that it is a folding intermediate (rather than the native form) that polymerises, and it is clear that this intermediate must have different structural properties to the native, folded state.

In 2008, a key serpin crystal structure was determined that strongly suggests that physiological serpin polymers do not form via the A-sheet mechanism and instead form via a more extensive domain swapping event.[12] The first such structure solved was of an antithrombin dimer (figure 10), and revealed that both strands s5A and the RCL can be incorporated into the A-sheet of another serpin molecule. This structure can readily be adapted to form long chain polymers.[12] In 2011, the structure of a domain swapped antitrypsin trimer revealed that in polymers of this serpin the RCL is inserted, and that the C-terminal region of the molecule (comprising strands s1C, s4B and s5B) formed the domain swap (figure 11).[63] In support of the physiological relevance of the latter structure, it was shown that antitrypsin polymers formed via a C-terminal domain swap were recognised by a monocloncal antibody[64] specific for pathogenic antitrypsin polymers.[63]

Figure 11: The structure of an antitrypsin trimer formed via domain swapping of the C-terminal region.[63] In the green molecule the inserted RCL is shown in red (pdb code 3T1P). The region that is domain swapped into the neighbouring molecule comprises s1C, s4B and s5B.

The new "domain swapped" model for serpin polymerisation begins to reconcile the available biophysical and biochemical data. Together, these data suggest that domain swapping events occur when mutations or environmental factors somehow interfere with the final stages of serpin folding to the native state. These data also reveal that different serpins can apparently polymerise via different types of domain swaps. Finally, while these data shed light on the final polymeric form, it is important to note that the precise toxic species of intermediate and / or polymer that causes cell death in, for example, antitrypsin deficiency, remains to be identified.[65]

Development of therapeutic strategies to combat serpinopathies

Several therapeutic approaches are in use or under investigation to treat the most common serpinopathy; antitrypsin deficiency. Antitrypsin augmentation therapy is approved for severe antitrypsin deficiency-related pulmonary emphysema.[66] Lung and / or liver transplantation is also used to treat severe antitrypsin deficiency-related disease.[67] In animal models, gene targeting in induced pluripotent stem cells has successfully been deployed to correct the Z-antitrypsin defect and to restore the ability of the mammalian liver to secrete active antitrypsin.[68] A number of groups have also reported small molecules that block antitrypsin polymerisation in vitro.[69][70]

Mutations that result in spontaneous formation of latent (or latent-like), inactive conformations

Figure 12: X-ray crystal structure of the δ-conformation of the Leucine 55 to Proline mutation of antichymotrypsin (from pdb 1QMN). Four residues of the RCL (magenta; dashed line indicates disordered region) are inserted into the top of the A β-sheet. Part of the F α-helix (cyan) has unwound and fills the bottom half of the A β-sheet.[71]

Certain pathogenic mutations in serpins can promote inappropriate transition to the monomeric latent state (see figure 8a for the structure of the latent state). This causes disease because it reduces the amount of active inhibitory serpin. For example, the disease-linked antithrombin variants wibble and wobble,[72] both promote formation of the latent state.

It is also worth highlighting a structure of a disease-linked human antichymotrypsin variant that further demonstrates the extraordinary flexibility of the serpin scaffold. The structure of antichymotrypsin (Leucine 55 to Proline) revealed a novel "δ" conformation that may represent an intermediate between the native and latent state (Figure 12). In the delta conformation, four residues of the RCL are inserted into the top of β-sheet A. The bottom half of the sheet is filled as a result of one of the α-helices (the F-helix) partially switching to a β-strand conformation, completing the β-sheet hydrogen bonding.[71] It is unclear whether other serpins can adopt this conformer, and whether this conformation has a functional role. However, it is speculated that the δ-conformation may be adopted by Thyroxine-binding globulin during thyroxine release.[26]

In humans, simple deficiency of many serpins (e.g., through a null mutation) may result in disease (see Table 1).

It is rare that single amino acid changes in the RCL of a serpin alters the specificity of the inhibitor and allow it to target the wrong protease. For example, the Antitrypsin-Pittsburgh mutation (methionine 358 to arginine) allowed the serpin to inhibit thrombin, thus causing a bleeding disorder.[73]

Serpins are suicide inhibitors, the RCL acting as a "bait." Certain disease-linked mutations in the RCL of human serpins permit true substrate-like behaviour and cleavage without complex formation. Such variants are speculated to affect the rate or the extent of RCL insertion into the A-sheet. These mutations, in effect, result in serpin deficiency through a failure to properly control the target protease.[58][74]

Several non-inhibitory serpins play key roles in important human diseases. For example, mutations in SERPINF1 cause osteogenesis imperfecta type VI in humans.[75]

Evolution

Serpins were initially believed to be restricted to eukaryote organisms, but have since been found in a number of bacteria and archaea.[6][7][76] It remains unclear whether these prokaryote genes are the descendants of an ancestral prokaryotic serpin or the product of lateral gene transfer (genetic transfer between organisms not by evolutionary descent). Rawlings et al. showed that serpins are the most widely distributed and largest family of protease inhibitors.[9]

Types of serpins

Human

In 2001, a serpin nomenclature was established (see table 1, below).[10] The naming system is based upon a phylogenetic analysis of ~500 serpins.[6] The human genome encodes 16 serpin clades, termed serpinA through to serpinP, encoding 29 inhibitory and 7 non-inhibitory serpin proteins (see Law et al. (2006) & Heit et al. (2013) for recent reviews).[77][78] The proteins are named serpinXY where X is the clade of the protein and Y the number of the protein within that clade. Table 1 lists each human serpin, together with brief notes in regards to each molecules function and the consequence (where known) of dysfunction or deficiency.

Table 1

Protein name PDB Common Name Description Disease / Effect of deficiency Chromosomal location
SERPINA1 1QLP
7API
1D5S		 Alpha 1-antitrypsin extracellular, inhibits human neutrophil elastase.[79] Deficiency results in emphysema, antitrypsin polymerisation results in cirrhosis. Serpinopathy.[14] The C-terminal fragment of cleaved SERPINA1 may inhibit HIV-1 infection.[80] 14q32.1
SERPINA2 Antitrypsin-related protein extracellular, possible pseudogene[81] Unknown 14q32.1
SERPINA3 1YXA[36]
2ACH[82]		 Alpha 1-antichymotrypsin Extracellular, inhibits cathepsin G.[83] Reported to play a role in controlling chromatin condensation in hepatic cells.[84] Deficiency results in emphysema. Serpinopathy[71] 14q32.1
SERPINA4 Kallistatin extracellular, inhibition of kallikrein, regulation of vascular function[85][86] Depletion of Kallistatin in hypertensive rats enhanced renal and cardiovascular injury.[87] 14q32.1
SERPINA5 2OL2[88]
3B9F[89]
 Protein C inhibitor Extracellular, inhibitor of active protein C.[90] Intracellular role in preventing phagocytosis of bacteria.[91] Male murine knockouts are infertile[92] In multiple sclerosis, accumulation of PCI has been noted in chronic active plaques.[93] 14q32.1
SERPINA6 2V6D[25]
2VDX
2VDY		 Cortisol binding globulin Extracellular, non-inhibitory; cortisol binding.[25] Deficiency may cause chronic fatigue[94] 14q32.1
SERPINA7 2CEO[26]
2RIV
2RIW
 Thyroxine-binding globulin extracellular, non-inhibitory; thyroxine binding[26] Deficiency causes hypothyroidism.[95] Xq22.2
SERPINA8 2X0B[96]
2WXW
2WXX
2WXY
2WXZ
2WY0
2WY1		 Angiotensinogen Extracellular; non-inhibitory, cleavage by renin results in release of angiotensin I.[97] Variants linked to hypertension[98] Murine knockouts result in hypotension.[99] 1q42-q43
SERPINA9 Centerin / GCET1 Extracellular; inhibitory, maintenance of naive B cells[100][101] Strongly expressed in most B-cell lymphomas.[102][103] 14q32.1
SERPINA10 3F1S[1]
3H5C[104][105]		 Protein Z-related protease inhibitor extracellular, binds protein Z and inactivates factor Xa and factor XIa[106] Deficiency may cause venous thromboembolic disease[107] 14q32.1
SERPINA11 - probably extracellular, not characterised. Unknown 14q32.13
SERPINA12 4IF8[108] Vaspin extracellular, insulin-sensitizing adipocytokine.[109] Inhibitor of Kallikrein-7 High plasma levels of SERPINA12 are correlated with insulin resistance in Type II Diabetes.[110] 14q32.1
SERPINA13 - probably extracellular, not characterised Unknown 14q32
SERPINB1 1HLE[111] Monocyte neutrophil elastase inhibitor Intracellular, inhibition of neutrophil elastase[112] Murine knockout results in neutrophil survival defect and immune deficiency[113] 6p25
SERPINB2 1BY7[114] Plasminogen activator inhibitor-2 Intracellular/extracellular. Inhibition of extracellular uPA. Intracellular function unclear, however, may protect against viral infection.[115] Murine knockouts viable / no obvious phenotype.[116] SERPINB2 deficient mice are less able to mount an immune response to nematode infection.[117] 18q21.3
SERPINB3 2ZV6[118] Squamous cell carcinoma antigen-1 (SCCA-1) Intracellular, inhibitor of papain-like cysteine proteases[19] Mice lacking Serpinb3a (the murine homolog of human SERPINB3 and SERPINB4) have reduced mucus production in a murine model of asthma.[119] 18q21.3
SERPINB4 Squamous cell carcinoma antigen-2 (SCCA-2) Intracellular, inhibitor of cathepsin G and chymase[120] Mice lacking Serpinb3a (the murine homolog of human SERPINB3 and SERPINB4) have reduced mucus production in a murine model of asthma.[119] 18q21.3
SERPINB5 1WZ9[121] Maspin Obligate intracellular serpin,[122] non inhibitory, originally proposed to function as a tumour suppressor.[123] Another study was unable to reproduce these findings and found no role for maspin in tumour biology.[124] Murine maspin knockouts originally reported to be lethal,[125] A subsequent study, however, reported that maspin knockout mice are viable and display no obvious phenotype.[124] From a disease perspective is suggested that maspin may be a prognostic indicator that reflects expression of a neighbouring known tumour suppressor gene (the phosphatase PHLPP1).[124] 18q21.3
SERPINB6 PI-6 intracellular, inhibition of cathepsin G[126] Murine knockout reveals mild neutropenia.[127] In humans, a nonsense mutation in SERPINB6 results in moderate to severe hearing loss.[128][129] 6p25
SERPINB7 Megsin intracellular, involved in megakaryocyte maturation[130] Studies on transgenic mice reveal megsin over-expression causes kidney disease.[131] Histological abnormalities are, however, not apparent in Megsin knockout mice.[131] Mutations in humans are associated with Nagashima-type Palmoplantar Keratosis[132][133] 18q21.3
SERPINB8 PI-8 intracellular; possible furin inhibitor[134] Genome wide association studies suggest that the SERPINB8 locus is linked with the development of Psoriasis.[135][136] 18q21.3
SERPINB9 PI-9 intracellular, inhibitor of the cytotoxic granule protease granzyme B[137] murine knockout reveals immune dysfunction[138][139] 6p25
SERPINB10 Bomapin intracellular, unknown function[140] Analysis of murine genomic material (C57/BL6; the common lab strain) reveals a stop codon in this gene (BC069938). In contrast, EST data suggests that full length bomapin is expressed in Czech II mice. These data suggest that loss of Bomapin function in mice does not result in an overt phenotype. 18q21.3
SERPINB11 intracellular, unknown function[141] Murine Serpinb11 is an active inhibitor whereas the human orthalogue is inactive.[141] Serpinb11 deficiency is associated with hoof wall separation disease in Connemara Ponies.[142] 18q21.3
SERPINB12 Yukopin intracellular, unknown function[143] Unknown 18q21.3
SERPINB13 Hurpin/Headpin intracellular, inhibitor of papain-like cysteine proteases[144] Unknown 18q21.3
SERPINC1 2ANT
2ZNH
1AZX
1TB6
2GD4
1T1F		 Antithrombin Extracellular, inhibitor of coagulation, specifically factor X, factor IX and thrombin[145] Deficiency results in thrombosis and other clotting disorders. Serpinopathy[146] 1q23-q21
SERPIND1 1JMJ
1JMO[147]		 Heparin cofactor II extracellular, thrombin inhibitor[148] Murine knockouts are lethal.[149] 22q11
SERPINE1 1DVN[150]
1OC0[151]		 Plasminogen activator inhibitor 1 Extracellular; inhibitor of thrombin, uPA and TPa.[152] Cardiovascular disease, tumour progression[153][154] 7q21.3-q22
SERPINE2 4DY0[155] Glia derived nexin / Protease nexin I Extracellular, inhibition of uPA and tPA.[156] Abnormal expression leads to human male infertility.[157] Knockout mice also develop epileptic phenotype.[158] 2q33-q35
SERPINF1 1IMV[159] Pigment epithelium derived factor Extracellular, non-inhibitory, potent anti-angiogenic molecule.[160] PEDF has been reported to bind the glycosaminoglycan hyaluronan.[161] Murine knockout studies reveal that SERPINF1 regulates the vasculature and mass of the pancreas and the prostate.[160] Further, SERPINF1 has been demonstrated to promote Notch–dependent renewal of adult periventricular neural stem cells.[162] Human mutations in SERPINF1 cause osteogenesis imperfecta type VI.[75] 17p13.3
SERPINF2 2R9Y[163] Alpha 2-antiplasmin extracellular, plasmin inhibitor, inhibitor of fibrinolysis.[164] Bleeding disorder[165] 17pter-p12
SERPING1 2OAY[166] Complement 1-inhibitor Extracellular, C1 esterase inhibitor.[166] Angiodemia, serpinopathy.[167] Several polymorphisms in the SERPING1 gene are strongly associated with development of age-related macular degeneration and blindness.[168] 11q11-q13.1
SERPINH1 4AXY[169] 47 kDa Heat shock protein (HSP47) intracellular, non inhibitory, molecular chaperone in collagen folding.[170] Murine knockouts are lethal.[171] A missense mutation in human SERPINH1 results in severe osteogenesis imperfecta.[172][173] 11p15
SERPINI1 1JJO
3FGQ[174]
3F5N
3F02[175]		 Neuroserpin Extracellular, inhibitor of tPA, uPA and plasmin[176] Mutated in dementia (FENIB). Serpinopathy[177] 3q26
SERPINI2 Pancpin Extracellular, unknown protease target.[178] Studies on the Pequeño mouse line revealed that loss of SERPINI2 results in pancreatic insufficiency through pancreatic acinar cell loss.[179] In addition a possible role for SERPINI2 in inhibition of pancreatic cancer metastasis has been suggested.[178] 3q26

Specialised Mammalian Serpins

Many mammalian serpins have been identified that share no obvious orthology with a human serpin counterpart. Examples include numerous rodent serpins (particularly some of the murine intracellular serpins) as well as the uterine serpins (discussed below).

Uterine

The term uterine serpin refers to members of the serpin A clade that are encoded by the SERPINA14 gene. Uterine serpins are produced by the uterine endometrium of a restricted group of mammals in the Laurasiatheria clade under the influence of progesterone or estrogen.[180] They are probably not functional proteinase inhibitors and may function during pregnancy to inhibit maternal immune responses against the conceptus or to participate in transplacental transport.[181]

Insect

The Drosophila melanogaster genome contains 29 serpin encoding genes. Amino acid sequence analysis has placed 14 of these serpins in serpin clade Q and 3 in serpin clade K with the remaining 12 serpins classified as orphan serpins not belonging to any clade.[182] The clade classification system is difficult to use for Drosophila serpins and instead a nomenclature system has been adopted that is based on the position of Drosphila serpin genes on the Drosophila chromosomes. 13 of the Drosophila serpins occur as isolated genes in the genome (including Serpin-27A, see below), with the remaining 16 organised into three gene clusters that occur at chromosome positions 28D (2 serpins), 42D (5 serpins), 43A (4 serpins), 77B (3 serpins) and 88E (2 serpins).[182][183][184]

Studies on Drosophila serpins reveal that Serpin-27A inhibits the Easter protease (the final protease in the Nudel, Gastrulation Defective, Snake and Easter proteolytic cascade) and thus controls dorsoventral patterning. Easter functions to cleave Spätzle (a chemokine-type ligand), which results in Toll mediated signaling. In addition to its central role in embryonic patterning, Toll signaling is also important for the innate immune response in insects. Accordingly, serpin-27A additionally functions to control the insect immune response.[185][186][187] In Tenebrio molitor (a large beetle), a protein (SPN93) comprising two discrete tandem serpin domains functions to regulate the toll proteolytic cascade.[188]

Worm

The genome of the nematode worm C. elegans contains nine serpins, however, only five of these molecules appear to function as protease inhibitors.[30] One of these serpins, SRP-6, has been shown to perform a protective function and guard against stress induced calpain-associated lysosomal disruption. Further SRP-6 functions to inhibit lysosomal cysteine proteases released after lysosomal rupture. Accordingly, worms lacking SRP-6 are sensitive to stress. Most notably, SRP-6 knockout worms die when placed in water (the hypo-osmotic stress lethal phenotype or Osl). Based on these data it is suggested that lysosomes play a general and controllable role in determining cell fate.[189]

Plant

The presence of serpins in plants has long been recognised,[190] indeed, an abundant barley grain serpin (barley Protein Z) is one of the major protein components in beer.

The MEROPS database identifies 18 serpin family members in the Arabidopsis thaliana genome, but only about eight of these are full-length serpin sequences. Plant serpins are potent inhibitors of mammalian chymotrypsin-like serine proteases in vitro, the most well-studied example being barley serpin Zx (BSZx), which is able to inhibit trypsin, chymotrypsin as well as several blood coagulation factors.[191] However, close relatives of chymotrypsin-like serine proteases are absent in plants. The RCL of several serpins from wheat grain and rye [192] contain poly-Q repeat sequences similar to those present in the prolamin storage proteins of the endosperm.[193] It has therefore been suggested that plant serpins may function to inhibit proteases from insects or microbes that cleave grain storage proteins. In support of this hypothesis, specific plant serpins have been identified in the phloem sap of pumpkin (CmPS-1)[194] and cucumber plants.[195][196] However, while an inverse correlation between up-regulation of CmPS-1 expression and aphid survival was observed, in vitro feeding experiments revealed that recombinant CmPS-1 did not appear to affect insect survival.[194]

Alternative roles and protease targets for plant serpins have been proposed. It has been shown that Arabidopsis AtSerpin1 (At1g47710; 3LE2[24]) inhibits metacaspase-like proteases in vitro.[23] More recently, the major in vivo protease target for AtSerpin1 was identified as the papain-like cysteine protease RESPONSIVE TO DESICCATION-21 (RD21). Through this activity, AtSerpin1 was shown to exert set-point control over programmed cell death in Arabidopsis.[197]

Two other Arabidopsis serpins, AtSRP2 (At2g14540) and AtSRP3 (At1g64030) appear to be involved in responses to DNA damage caused by plant exposure to methane methylsulfonate (MMS).[198]

Fungal

A single fungal serpin has been characterized to date: celpin from Piromyces sp. strain E2. Piromyces is an anaerobic fungus found in the gut of ruminants and is important for digesting plant material. Celpin is predicted to be an inhibitory molecule and contains two N-terminal dockerin domains in addition to the serpin domain. Dockerins are commonly found in proteins that localise to the fungal cellulosome, a large extracellular multiprotein complex that breaks down cellulose.[8] It is therefore suggested that celpin protects the cellulosome against plant proteases. Certain bacterial serpins also localize to the cellulosome.[199]

Prokaryote

Predicted serpin genes are sporadically distributed in prokaryotes. In vitro studies on some of these molecules have revealed that they are able to inhibit proteases and it is suggested that they function as inhibitors in vivo. Several prokaryote serpins are found in extremophiles. Accordingly, and in contrast to mammalian serpins, these molecule possess elevated resistance to heat denaturation.[200][201] The precise role of most bacterial serpins remains obscure, however, Clostridium thermocellum serpin localises to the cellulosome. It is suggested that the role of cellulosome-associated serpins may be to prevent unwanted protease activity against the cellulosome.[199]

Viral

Serpins are also expressed by viruses as a way to evade the host's immune defense.[202] In particular, serpins expressed by pox viruses, including cow pox (vaccinia) and rabbit pox (myxoma), are of interest because of their potential use as novel therapeutics for immune and inflammatory disorders as well as transplant therapy.[203][204] A study on Serp1 reveals this molecule suppresses the Toll-mediated innate immune response and allows indefinite cardiac allograft survival in rats.[203][205] Studies on Crma and Serp2, reveal both are cross-class inhibitor and targets both serine (Granzyme B; albeit weakly) and cysteine proteases (Caspase 1 and Caspase 8).[206][207] In comparison to their mammalian counterparts, viral serpins contain significant deletions of elements of secondary structure. Specifically, structural studies on crmA reveals this molecule lacks the D-helix as well as significant portions of the A- and E-helices.[208]

See also

References

  1. ^ a b Wei Z, Yan Y, Carrell RW, Zhou A (June 2009). "Crystal structure of protein Z–dependent inhibitor complex shows how protein Z functions as a cofactor in the membrane inhibition of factor X". Blood. 114 (17): 3662–7. doi:10.1182/blood-2009-04-210021. PMC 2766681. PMID 19528533.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ R. Carrell and J. Travis. (1985). "α1-Antitrypsin and the serpins: Variation and countervariation". Trends Biochem. Sci. 10: 20–24. doi:10.1016/0968-0004(85)90011-8.
  3. ^ Whisstock JC, Silverman GA, Bird PI, Bottomley SP, Kaiserman D, Luke CJ, Pak SC, Reichhart JM, Huntington JA (May 2010). "Serpins Flex Their Muscle: II. STRUCTURAL INSIGHTS INTO TARGET PEPTIDASE RECOGNITION, POLYMERIZATION, AND TRANSPORT FUNCTIONS". J Biol Chem. 285 (32): 24307–12. doi:10.1074/jbc.R110.141408. PMC 2915666. PMID 20498368.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  4. ^ Silverman GA, Whisstock JC, Bottomley SP, Huntington JA, Kaiserman D, Luke CJ, Pak SC, Reichhart JM, Bird PI (May 2010). "Serpins Flex Their Muscle: I. PUTTING THE CLAMPS ON PROTEOLYSIS IN DIVERSE BIOLOGICAL SYSTEMS". J Biol Chem. 285 (32): 24299–305. doi:10.1074/jbc.R110.112771. PMC 2915665. PMID 20498369.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  5. ^ Hunt LT, Dayhoff MO (1980). "A surprising new protein superfamily containing ovalbumin, antithrombin-III, and α1-proteinase inhibitor". Biochem. Biophys. Res. Commun. 95 (2): 864–71. doi:10.1016/0006-291X(80)90867-0. PMID 6968211.
  6. ^ a b c Irving JA, Pike RN, Lesk AM, Whisstock. (2000). "Phylogeny of the Serpin Superfamily: Implications of Patterns of Amino Acid Conservation for Structure and Function". Genome Res. 10 (12): 1845–64. doi:10.1101/gr.GR-1478R. PMID 11116082.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ a b Irving J, Steenbakkers P, Lesk A, Op den Camp H, Pike R, Whisstock J (2002). "Serpins in prokaryotes". Mol Biol Evol. 19 (11): 1881–90. doi:10.1093/oxfordjournals.molbev.a004012. PMID 12411597.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  8. ^ a b Steenbakkers PJ, Irving JA, Harhangi HR, et al. (August 2008). "A serpin in the cellulosome of the anaerobic fungus Piromyces sp. strain E2". Mycol. Res. 112 (Pt 8): 999–1006. doi:10.1016/j.mycres.2008.01.021. PMID 18539447.
  9. ^ a b Rawlings ND, Tolle DP, Barrett AJ. (2004). "Evolutionary families of peptidase inhibitors". Biochem J. 378 (Pt 3): 705–16. doi:10.1042/BJ20031825. PMC 1224039. PMID 14705960.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ a b Silverman GA, Bird PI, Carrell RW, Church FC, Coughlin PB, Gettins PG, Irving JA, Lomas DA, Luke CJ, Moyer RW, Pemberton PA, Remold-O'Donnell E, Salvesen GS, Travis J, Whisstock JC. (2001). "'The serpins are an expanding superfamily of structurally similar but functionally diverse proteins. Evolution, mechanism of inhibition, novel functions, and a revised nomenclature". J Biol Chem. 276 (36): 33293–6. doi:10.1074/jbc.R100016200. PMID 11435447.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  11. ^ a b c Huntington J, Read R, Carrell R (2000). "Structure of a serpin-protease complex shows inhibition by deformation". Nature. 407 (6806): 923–6. doi:10.1038/35038119. PMID 11057674.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ a b c d Yamasaki M, Li W, Johnson DJ, Huntington JA (October 2008). "Crystal structure of a stable dimer reveals the molecular basis of serpin polymerization". Nature. 455 (7217): 1255–8. doi:10.1038/nature07394. PMID 18923394.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ a b c d Carrell RW, Lomas DA. (1997). "Conformational disease". Lancet. 350 (9071): 134–8. doi:10.1016/S0140-6736(97)02073-4. PMID 9228977.
  14. ^ a b c d e f Lomas DA, Evans DL, Finch JT & Carrell RW (1992). "The mechanism of Z alpha 1-antitrypsin accumulation in the liver". Nature. 357 (6379): 605–607. doi:10.1038/357605a0. PMID 1608473.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Tsukada H, Blow DM (1985). "Structure of alpha-chymotrypsin refined at 1.68 A resolution". J. Mol. Biol. 184 (4): 703–11. doi:10.1016/0022-2836(85)90314-6. PMID 4046030.
  16. ^ Barrett AJ, Rawlings ND. (1995). "Families and clans of serine peptidases". Arch Biochem Biophys. 318 (2): 247–50. doi:10.1006/abbi.1995.1227. PMID 7733651.
  17. ^ Barrett AJ, Rawlings ND. (2001). "Evolutionary lines of cysteine peptidases". Biol Chem. 382 (5): 727–33. doi:10.1515/BC.2001.088. PMID 11517925.
  18. ^ Irving JA, Pike RN, Dai W, Bromme D, Worrall DM, Silverman GA, Coetzer TH, Dennison C, Bottomley SP, Whisstock JC. (2002). "Evidence that serpin architecture intrinsically supports papain-like cysteine protease inhibition: engineering alpha(1)-antitrypsin to inhibit cathepsin proteases". Biochemistry. 41 (15): 4998–5004. doi:10.1021/bi0159985. PMID 11939796.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ^ a b Schick C, Brömme D, Bartuski A, Uemura Y, Schechter N, Silverman G (1998). "The reactive site loop of the serpin SCCA1 is essential for cysteine proteinase inhibition". Proc. Natl. Acad. Sci. U.S.A. 95 (23): 13465–70. doi:10.1073/pnas.95.23.13465. PMC 24842. PMID 9811823.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  20. ^ a b McGowan S, Buckle A, Irving J, Ong P, Bashtannyk-Puhalovich T, Kan W, Henderson K, Bulynko Y, Popova E, Smith A, Bottomley S, Rossjohn J, Grigoryev S, Pike R, Whisstock J (2006). "X-ray crystal structure of MENT: evidence for functional loop–sheet polymers in chromatin condensation". The EMBO Journal. 25 (13): 3144–55. doi:10.1038/sj.emboj.7601201. PMC 1500978. PMID 16810322.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ Ong PC, McGowan S, Pearce MC, Irving JA, Kan WT, Grigoryev SA, Turk B, Silverman GA, Brix K, Bottomley SP, Whisstock JC, Pike RN (2007). "DNA accelerates the inhibition of human cathepsin V by serpins". Journal of Biological Chemistry. 282 (51): 36980–6. doi:10.1074/jbc.M706991200. PMID 17923478.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  22. ^ Ray C, Black R, Kronheim S, Greenstreet T, Sleath P, Salvesen G, Pickup D (1992). "Viral inhibition of inflammation: cowpox virus encodes an inhibitor of the interleukin-1 beta converting enzyme". Cell. 69 (4): 597–604. doi:10.1016/0092-8674(92)90223-Y. PMID 1339309.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  23. ^ a b Vercammen D, Belenghi B, van de Cotte B, Beunens T, Gavigan JA, De Rycke R, Brackenier A, Inze D, Harris JL, Van Breusegem F. (2006). "Serpin1 of Arabidopsis thaliana is a suicide inhibitor for metacaspase 9". J Mol Biol. 364 (4): 625–36. doi:10.1016/j.jmb.2006.09.010. PMID 17028019.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  24. ^ a b Lampl N, Budai-Hadrian O, Davydov O, Joss TV, Harrop SJ, Curmi PM, Roberts TH, Fluhr R. (2010). "Arabidopsis AtSerpin1, Crystal Structure and in Vivo Interaction with Its Target Protease RESPONSIVE TO DESICCATION-21 (RD21)". J Biol. Chem. 285 (18): 13550–60. doi:10.1074/jbc.M109.095075. PMC 2859516. PMID 20181955.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  25. ^ a b c d e Klieber MA, Underhill C, Hammond GL, Muller YA. (2007). "Corticosteroid-binding globulin: structural basis for steroid transport and proteinase-triggered release". J Biol Chem. 282 (40): 29594–603. doi:10.1074/jbc.M705014200. PMID 17644521.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  26. ^ a b c d e Zhou A, Wei Z, Read RJ, Carrell RW. (2006). "Structural mechanism for the carriage and release of thyroxine in the blood". Proc. Natl. Acad. Sci. U.S.A. 103 (=36): 13321–6. doi:10.1073/pnas.0604080103. PMC 1557382. PMID 16938877.{{cite journal}}: CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link)
  27. ^ Campbell DJ. (2003). "The renin-angiotensin and the kallikrein-kinin systems". Int J Biochem Cell Biol. 35 (6): 784–91. doi:10.1016/S1357-2725(02)00262-5. PMID 12676165.
  28. ^ Remold-O'Donnell E, Chin J, Alberts M. (1992). "Sequence and molecular characterization of human monocyte/neutrophil elastase inhibitor". Proc. Natl. Acad. Sci. U.S.A. 89 (12): 5635–9. doi:10.1073/pnas.89.12.5635. PMC 49347. PMID 1376927.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  29. ^ Coughlin P, Sun J, Cerruti L, Salem HH, Bird P., (1993). "Cloning and molecular characterization of a human intracellular serine proteinase inhibitor". Proc. Natl. Acad. Sci. U.S.A. 90 (20): 9417–21. doi:10.1073/pnas.90.20.9417. PMC 47579. PMID 8415716.{{cite journal}}: CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link)
  30. ^ a b Pak SC, Kumar V, Tsu C, Luke CJ, Askew YS, Askew DJ, Mills DR, Bromme D, Silverman GA. (2004). "SRP-2 is a cross-class inhibitor that participates in postembryonic development of the nematode Caenorhabditis elegans: initial characterization of the clade L serpins". J Biol Chem. 279 (15): 15448–59. doi:10.1074/jbc.M400261200. PMID 14739286.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  31. ^ Bird PI. (1999). "Regulation of pro-apoptotic leucocyte granule serine proteinases by intracellular serpins". Immunol Cell Biol. 77 (1): 47–57. doi:10.1046/j.1440-1711.1999.00787.x. PMID 10101686.
  32. ^ Bird CH, Sutton VR, Sun J, Hirst CE, Novak A, Kumar S, Trapani JA, Bird PI (1998). "Selective regulation of apoptosis: the cytotoxic lymphocyte serpin proteinase inhibitor 9 protects against granzyme B-mediated apoptosis without perturbing the Fas cell death pathway". Mol Cell Biol. 18 (11): 6387–98. PMID 9774654.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  33. ^ Grigoryev SA, Bednar J, Woodcock CL. (1999). "MENT, a heterochromatin protein that mediates higher order chromatin folding, is a new serpin family member". J Biol Chem. 274 (9): 5626–36. doi:10.1074/jbc.274.9.5626. PMID 10026180.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  34. ^ Tasab M, Batten MR, Bulleid NJ (2000). "Hsp47: a molecular chaperone that interacts with and stabilizes correctly-folded procollagen". EMBO J. 19 (10): 2204–11. doi:10.1093/emboj/19.10.2204. PMC 384358. PMID 10811611.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  35. ^ Elliott PR, Lomas DA, Carrell RW, Abrahams JP. (1996). "Inhibitory conformation of the reactive loop of alpha 1-antitrypsin". Nature Structural & Molecular Biology. 3 (8): 676–81. doi:10.1038/nsb0896-676. PMID 8756325.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  36. ^ a b Horvath AJ, Irving JA, Rossjohn J, Law RH, Bottomley SP, Quinsey NS, et al. (2005). "The murine orthologue of human antichymotrypsin: a structural paradigm for clade A3 serpins". J Biol Chem. 280 (52): 43168–78. doi:10.1074/jbc.M505598200. PMID 16141197.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  37. ^ a b Loebermann H, Tokuoka R, Deisenhofer J, Huber R. (1984). "Human alpha 1-proteinase inhibitor. Crystal structure analysis of two crystal modifications, molecular model and preliminary analysis of the implications for function". J Mol Biol. 177 (3): 531–57. doi:10.1016/0022-2836(84)90298-5. PMID 6332197.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  38. ^ Stein PE, Leslie AG, Finch JT, Turnell WG, McLaughlin PJ, Carrell RW. (1990). "Crystal structure of ovalbumin as a model for the reactive centre of serpins". Nature. 347 (6288): 99–102. doi:10.1038/347099a0. PMID 2395463.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  39. ^ a b Whisstock J, Bottomley S (2006). "Molecular gymnastics: serpin structure, folding and misfolding". Current Opinion in Structural Biology. 16 (6): 761–8. doi:10.1016/j.sbi.2006.10.005. PMID 17079131.
  40. ^ Egelund R, Rodenburg K, Andreasen P, Rasmussen M, Guldberg R, Petersen T (1998). "An ester bond linking a fragment of a serine proteinase to its serpin inhibitor". Biochemistry. 37 (18): 6375–9. doi:10.1021/bi973043. PMID 9572853.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  41. ^ Gettins P (2002). "Serpin structure, mechanism, and function". Chem Rev. 102 (12): 4751–804. doi:10.1021/cr010170. PMID 12475206.
  42. ^ Whisstock JC, Skinner R, Carrell RW, Lesk AM (2000). "Conformational changes in serpins: I. The native and cleaved conformations of alpha(1)-antitrypsin". J Mol Biol. 296 (2): 685–99. doi:10.1006/jmbi.1999.3520. PMID 10669617.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  43. ^ Ye S, Cech A, Belmares R, Bergstrom R, Tong Y, Corey D, Kanost M, Goldsmith E (2001). "The structure of a Michaelis serpin-protease complex". Nature Structural & Molecular Biology. 8 (11): 979–83. doi:10.1038/nsb1101-979. PMID 11685246.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  44. ^ Jin L, Abrahams JP, Skinner R, Petitou M, Pike RN, Carrell RW. (1997). "The anticoagulant activation of antithrombin by heparin". Proc. Natl. Acad. Sci. U.S.A. 94 (26): 14683–8. doi:10.1073/pnas.94.26.14683. PMC 25092. PMID 9405673.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  45. ^ Whisstock JC, Pike RN, Jin L, Skinner R, Pei XY, Carrell RW, Lesk AM. (2000). "Conformational changes in serpins: II. The mechanism of activation of antithrombin by heparin". J Mol Biol. 301 (5): 1287–305. doi:10.1006/jmbi.2000.3982. PMID 10966821.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  46. ^ Li W, Johnson DJ, Esmon CT, Huntington JA (2004). "Structure of the antithrombin-thrombin-heparin ternary complex reveals the antithrombotic mechanism of heparin". Nature Structural & Molecular Biology. 11 (9): 857–62. doi:10.1038/nsmb811. PMID 15311269.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  47. ^ Johnson DJ, Li W, Adams TE, Huntington JA (2006). "Antithrombin–S195A factor Xa-heparin structure reveals the allosteric mechanism of antithrombin activation". EMBO J. 25 (9): 2029–37. doi:10.1038/sj.emboj.7601089. PMC 1456925. PMID 16619025.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  48. ^ Petitou M, van Boeckel CA (2004). "A synthetic antithrombin III binding pentasaccharide is now a drug! What comes next?". Angew. Chem. Int. Ed. Engl. 43 (24): 3118–33. doi:10.1002/anie.200300640. PMID 15199558.
  49. ^ Lindahl T, Sigurdardottir O, Wiman B (1989). "Stability of plasminogen activator inhibitor 1 (PAI-1)". Thromb Haemost. 62 (2): 748–51. PMID 2479113.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  50. ^ Zhang Q, Buckle AM, Law RH, Pearce MC, Cabrita LD, Lloyd GJ, Irving JA, Smith AI, Ruzyla K, Rossjohn J, Bottomley SP, Whisstock JC. (2007). "The N terminus of the serpin, tengpin, functions to trap the metastable native state". EMBO Reports. 8 (7): 658–63. doi:10.1038/sj.embor.7400986. PMC 1905895. PMID 17557112.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  51. ^ Zhang Q, Law RH, Bottomley SP, Whisstock JC, Buckle AM (March 2008). "A structural basis for loop C-sheet polymerization in serpins". Journal of Molecular Biology. 376 (5): 1348–59. doi:10.1016/j.jmb.2007.12.050. PMID 18234218.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  52. ^ a b Cao C, Lawrence DA, Li Y, Von Arnim CA, Herz J, Su EJ, Makarova A, Hyman BT, Strickland DK, Zhang L. (2006). "Endocytic receptor LRP together with tPA and PAI-1 coordinates Mac-1-dependent macrophage migration". EMBO J. 25 (9): 1860–70. doi:10.1038/sj.emboj.7601082. PMC 1456942. PMID 16601674.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  53. ^ Jensen JK, Dolmer K, Gettins PG (May 2009). "Specificity of Binding of the Low Density Lipoprotein Receptor-related Protein to Different Conformational States of the Clade E Serpins Plasminogen Activator Inhibitor-1 and Proteinase Nexin-1". J. Biol. Chem. 284 (27): 17989–97. doi:10.1074/jbc.M109.009530. PMC 2709341. PMID 19439404.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  54. ^ Soukup SF, Culi J, Gubb D (June 2009). Rulifson, Eric (ed.). "Uptake of the Necrotic Serpin in Drosophila melanogaster via the Lipophorin Receptor-1". PLOS Genetics. 5 (6): e1000532. doi:10.1371/journal.pgen.1000532. PMC 2694266. PMID 19557185.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  55. ^ Pemberton PA, Stein PE, Pepys MB, Potter JM, Carrell RW (1988). "Hormone binding globulins undergo serpin conformational change in inflammation". Nature. 336 (6196): 257–8. doi:10.1038/336257a0. PMID 3143075.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  56. ^ Chang WS, Whisstock J, Hopkins PC, Lesk AM, Carrell RW, Wardell MR. (1997). "Importance of the release of strand 1C to the polymerization mechanism of inhibitory serpins". Protein Sci. 6 (1): 89–98. doi:10.1002/pro.5560060110. PMC 2143506. PMID 9007980.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  57. ^ Kroeger H, Miranda E, Macleod I, Perez J, Crowther DC, Marciniak SJ, Lomas DA (June 2009). "Endoplasmic Reticulum-associated Degradation (ERAD) and Autophagy Cooperate to Degrade Polymerogenic Mutant Serpins". J. Biol. Chem. 284 (34): 22793–802. doi:10.1074/jbc.M109.027102. PMC 2755687. PMID 19549782.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  58. ^ a b Stein PE, Carrell RW. (1995). "What do dysfunctional serpins tell us about molecular mobility and disease?". Nature Structural & Molecular Biology. 2 (2): 96–113. doi:10.1038/nsb0295-96. PMID 7749926.
  59. ^ a b Huntington JA, Pannu NS, Hazes B, Read RJ, Lomas DA, Carrell RW (October 1999). "A 2.6 A structure of a serpin polymer and implications for conformational disease". Journal of Molecular Biology. 293 (3): 449–55. doi:10.1006/jmbi.1999.3184. PMID 10543942.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  60. ^ a b Dunstone MA, Dai W, Whisstock JC, Rossjohn J, Pike RN, Feil SC, Le Bonniec BF, Parker MW & Bottomley SP (2000). "Cleaved antitrypsin polymers at atomic resolution". Protein Sci. 9 (2): 417–420. doi:10.1110/ps.9.2.417. PMC 2144548. PMID 10716194.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  61. ^ a b c Yu MH, Lee KN, Kim J (May 1995). "The Z type variation of human alpha 1-antitrypsin causes a protein folding defect". Nature Structural & Molecular Biology. 2 (5): 363–7. doi:10.1038/nsb0595-363. PMID 7664092.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  62. ^ Knaupp AS, Bottomley SP (September 2011). "Structural Change in β-Sheet A of Z α(1)-Antitrypsin Is Responsible for Accelerated Polymerization and Disease". J Mol Biol. 413 (4): 888–98. doi:10.1016/j.jmb.2011.09.013. PMID 21945526.
  63. ^ a b c Yamasaki M, Sendall TJ, Pearce MC, Whisstock JC, Huntington JA (September 2011). "Molecular basis of α(1)-antitrypsin deficiency revealed by the structure of a domain-swapped trimer". EMBO Reports. 12 (10): 1011–7. doi:10.1038/embor.2011.171. PMC 3185345. PMID 21909074.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  64. ^ Miranda E, Pérez J, Ekeowa UI, et al. (September 2010). "A novel monoclonal antibody to characterize pathogenic polymers in liver disease associated with alpha1-antitrypsin deficiency". Hepatology. 52 (3): 1078–88. doi:10.1002/hep.23760. PMID 20583215.
  65. ^ Bottomley SP (September 2011). "The structural diversity in α1-antitrypsin misfolding". EMBO Reports. 12 (10): 983–4. doi:10.1038/embor.2011.187. PMC 3185355. PMID 21921939.
  66. ^ Sandhaus RA (October 2004). "alpha1-Antitrypsin deficiency . 6: new and emerging treatments for alpha1-antitrypsin deficiency". Thorax. 59 (10): 904–9. doi:10.1136/thx.2003.006551. PMC 1746849. PMID 15454659.
  67. ^ Fregonese L, Stolk J (2008). "Hereditary alpha-1-antitrypsin deficiency and its clinical consequences". Orphanet J Rare Dis. 3: 16. doi:10.1186/1750-1172-3-16. PMC 2441617. PMID 18565211.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  68. ^ Yusa K, Rashid ST, Strick-Marchand H, et al. (October 2011). "Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells". Nature. 478 (7369): 391–4. doi:10.1038/nature10424. PMC 3198846. PMID 21993621.
  69. ^ Mallya M, Phillips RL, Saldanha SA, et al. (November 2007). "Small molecules block the polymerization of Z alpha1-antitrypsin and increase the clearance of intracellular aggregates". Journal of Medicinal Chemistry. 50 (22): 5357–63. doi:10.1021/jm070687z. PMC 2631427. PMID 17918823.
  70. ^ Gosai SJ, Kwak JH, Luke CJ, et al. (2010). "Automated high-content live animal drug screening using C. elegans expressing the aggregation prone serpin α1-antitrypsin Z". PLOS ONE. 5 (11): e15460. doi:10.1371/journal.pone.0015460. PMC 2980495. PMID 21103396.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  71. ^ a b c Gooptu B, Hazes B, Chang WS, Dafforn TR, Carrell RW, Read RJ, Lomas DA. (2000). "Inactive conformation of the serpin α1-antichymotrypsin indicates two-stage insertion of the reactive loop: Implications for inhibitory function and conformational disease". Proc. Natl. Acad. Sci. U.S.A. 97 (1): 67–72. doi:10.1073/pnas.97.1.67. PMC 26617. PMID 10618372.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  72. ^ Beauchamp NJ, Pike RN, Daly M, Butler L, Makris M, Dafforn TR, Zhou A, Fitton HL, Preston FE, Peake IR, Carrell RW (1998). "Antithrombins Wibble and Wobble (T85M/K): archetypal conformational diseases with in vivo latent-transition, thrombosis, and heparin activation". Blood. 92 (8): 2696–706. PMID 9763552.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  73. ^ Owen MC, Brennan SO, Lewis JH, Carrell RW. (1983). "Mutation of antitrypsin to antithrombin. alpha 1-antitrypsin Pittsburgh (358 Met leads to Arg), a fatal bleeding disorder". N Engl J Med. 309 (12): 694–8. doi:10.1056/NEJM198309223091203. PMID 6604220.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  74. ^ Hopkins PC, Carrell RW, Stone SR. (1993). "Effects of mutations in the hinge region of serpins". Biochemistry. 32 (30): 7650–7. doi:10.1021/bi00081a008. PMID 8347575.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  75. ^ a b Homan EP, Rauch F, Grafe I, et al. (August 2011). "Mutations in SERPINF1 Cause Osteogenesis Imperfecta Type VI". J Bone Miner Res. 26 (12): 2798–803. doi:10.1002/jbmr.487. PMC 3214246. PMID 21826736.
  76. ^ Cabrita LD, Irving JA, Pearce MC, Whisstock JC, Bottomley SP. (2007). "Aeropin from the extremophile Pyrobaculum aerophilum bypasses the serpin misfolding trap". J Biol Chem. 282 (37): 26802–9. doi:10.1074/jbc.M705020200. PMID 17635906.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  77. ^ Law RH, Zhang Q, McGowan S, Buckle AM, Silverman GA, Wong W, Rosado CJ, Langendorf CG, Pike RN, Bird PI, Whisstock JC (2006). "An overview of the serpin superfamily". Genome Biol. 7 (5): 216. doi:10.1186/gb-2006-7-5-216. PMC 1779521. PMID 16737556.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  78. ^ Heit, C; Jackson, BC; McAndrews, M; Wright, MW; Thompson, DC; Silverman, GA; Nebert, DW; Vasiliou, V (Oct 30, 2013). "Update of the human and mouse SERPIN gene superfamily". Human genomics. 7: 22. doi:10.1186/1479-7364-7-22. PMC 3880077. PMID 24172014.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  79. ^ Stoller JK, Aboussouan LS (2005). "Alpha1-antitrypsin deficiency". Lancet. 365 (9478): 2225–36. doi:10.1016/S0140-6736(05)66781-5. PMID 15978931.
  80. ^ Munch J, Standker L, Adermann K, Schulz A, Schindler M, Chinnadurai R, Pohlmann S, Chaipan C, Biet T, Peters T, Meyer B, Wilhelm D, Lu H, Jing W, Jiang S, Forssmann WG, Kirchhoff F. (2007). "Discovery and optimization of a natural HIV-1 entry inhibitor targeting the gp41 fusion peptide". Cell. 129 (2): 263–75. doi:10.1016/j.cell.2007.02.042. PMID 17448989.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  81. ^ Seixas S, Suriano G, Carvalho F, Seruca R, Rocha J, Di Rienzo A. (2007). "Sequence Diversity at the Proximal 14q32.1 SERPIN Subcluster: Evidence for Natural Selection Favoring the Pseudogenization of SERPINA2". Mol Biol Evol. 24 (2): 587–98. doi:10.1093/molbev/msl187. PMID 17135331.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  82. ^ Baumann U, Huber R, Bode W, Grosse D, Lesjak M, Laurell CB (April 1991). "Crystal structure of cleaved human alpha 1-antichymotrypsin at 2.7 A resolution and its comparison with other serpins". J. Mol. Biol. 218 (3): 595–606. doi:10.1016/0022-2836(91)90704-A. PMID 2016749.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  83. ^ Kalsheker NA (1996). "Alpha 1-antichymotrypsin". Int. J. Biochem. Cell Biol. 28 (9): 961–4. doi:10.1016/1357-2725(96)00032-5. PMID 8930118.
  84. ^ Santamaria M, Pardo-Saganta A, Alvarez-Asiain L, Di Scala M, Qian C, Prieto J, et al. (2013). "Nuclear α1-antichymotrypsin promotes chromatin condensation and inhibits proliferation of human hepatocellular carcinoma cells". Gastroenterology. 144 (4): 818–828.e4. doi:10.1053/j.gastro.2012.12.029. PMID 23295442.
  85. ^ Chao J, Stallone JN, Liang YM, Chen LM, Wang DZ, Chao L (July 1997). "Kallistatin is a potent new vasodilator". J. Clin. Invest. 100 (1): 11–7. doi:10.1172/JCI119502. PMC 508159. PMID 9202051.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  86. ^ Miao RQ, Agata J, Chao L, Chao J. (2002). "Kallistatin is a new inhibitor of angiogenesis and tumor growth". Blood. 100 (9): 3245–52. doi:10.1182/blood-2002-01-0185. PMID 12384424.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  87. ^ Liu Y, Bledsoe G, Hagiwara M, Shen B, Chao L, Chao J (July 2012). "Depletion of endogenous kallistatin exacerbates renal and cardiovascular oxidative stress, inflammation and organ remodeling". Am J Physiol Renal Physiol. 303 (8): F1230–8. doi:10.1152/ajprenal.00257.2012. PMID 22811485.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  88. ^ Li W, Adams TE, Kjellberg M, Stenflo J, Huntington JA. (2007). "Structure of native protein C inhibitor provides insight into its multiple functions". FOOBAR. 282 (18): 13759–68. doi:10.1074/jbc.M701074200. PMID 17337440.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  89. ^ Li W, Adams TE, Nangalia J, Esmon CT, Huntington JA. (2008). "Molecular basis of thrombin recognition by protein C inhibitor revealed by the 1.6-A structure of the heparin-bridged complex". Proc. Natl. Acad. Sci. U.S.A. 105 (12): 4661–6. doi:10.1073/pnas.0711055105. PMC 2290767. PMID 18362344.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  90. ^ Geiger M (2007). "Protein C inhibitor, a serpin with functions in- and outside vascular biology". Thromb. Haemost. 97 (3): 343–7. doi:10.1160/th06-09-0488. PMID 17334499.
  91. ^ Baumgärtner P, Geiger M, Zieseniss S, Malleier J, Huntington JA, Hochrainer K, Bielek E, Stoeckelhuber M, Lauber K, Scherfeld D, Schwille P, Wäldele K, Beyer K, Engelmann B (2007). "Phosphatidylethanolamine critically supports internalization of cell-penetrating protein C inhibitor". J. Cell Biol. 179 (4): 793–804. doi:10.1083/jcb.200707165. PMC 2080921. PMID 18025309.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  92. ^ Uhrin P, Dewerchin M, Hilpert M, Chrenek P, Schofer C, Zechmeister-Machhart M, Kronke G, Vales A, Carmeliet P, Binder BR, Geiger M. (2000). "Disruption of the protein C inhibitor gene results in impaired spermatogenesis and male infertility". J Clin Invest. 106 (12): 1531–9. doi:10.1172/JCI10768. PMC 381472. PMID 11120760.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  93. ^ Han MH, Hwang SI, Roy DB, Lundgren DH, Price JV, Ousman SS, Fernald GH, Gerlitz B, Robinson WH, Baranzini SE, Grinnell BW, Raine CS, Sobel RA, Han DK, Steinman L (2008). "Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets". Nature. 451 (7182): 1076–81. doi:10.1038/nature06559. PMID 18278032.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  94. ^ Torpy DJ, Bachmann AW, Gartside M, Grice JE, Harris JM, Clifton P, Easteal S, Jackson RV, Whitworth JA. (2004). "Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism". Endocr Res. 30 (3): 417–29. doi:10.1081/ERC-200035599. PMID 15554358.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  95. ^ Bartalena L, Robbins J. (1992). "Variations in thyroid hormone transport proteins and their clinical implications". Thyroid. 2 (3): 237–45. doi:10.1089/thy.1992.2.237. PMID 1422238.
  96. ^ Zhou A, Carrell RW, Murphy MP, et al. (November 2010). "A redox switch in angiotensinogen modulates angiotensin release". Nature. 468 (7320): 108–11. doi:10.1038/nature09505. PMC 3024006. PMID 20927107.
  97. ^ Kumar R, Singh VP, Baker KM (2007). "The intracellular renin-angiotensin system: a new paradigm". Trends Endocrinol. Metab. 18 (5): 208–14. doi:10.1016/j.tem.2007.05.001. PMID 17509892.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  98. ^ Jeunemaitre X, Gimenez-Roqueplo AP, Celerier J, Corvol P. (1999). "Angiotensinogen variants and human hypertension". Curr Hypertens Rep. 1 (1): 31–41. doi:10.1007/s11906-999-0071-0. PMID 10981040.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  99. ^ Tanimoto K, Sugiyama F, Goto Y, Ishida J, Takimoto E, Yagami K, Fukamizu A, Murakami K (1994). "Angiotensinogen-deficient mice with hypotension". J. Biol. Chem. 269 (50): 31334–7. PMID 7989296.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  100. ^ Frazer JK, Jackson DG, Gaillard JP, Lutter M, Liu YJ, Banchereau J, Capra JD, Pascual V. (2000). "Identification of centerin: a novel human germinal center B cell-restricted serpin". Eur. J. Immunol. 30 (10): 3039–48. doi:10.1002/1521-4141(200010)30:10<3039::AID-IMMU3039>3.0.CO;2-H. PMID 11069088.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  101. ^ Paterson MA, Horvath AJ, Pike RN, Coughlin PB. (2007). "Molecular characterization of centerin, a germinal centre cell serpin". Biochem J. 405 (3): 489–94. doi:10.1042/BJ20070174. PMC 2267310. PMID 17447896.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  102. ^ Montes-Moreno S, Roncador G, Maestre L, et al. (January 2008). "Gcet1 (centerin), a highly restricted marker for a subset of germinal center-derived lymphomas". Blood. 111 (1): 351–8. doi:10.1182/blood-2007-06-094151. PMID 17898315.
  103. ^ Paterson MA, Hosking PS, Coughlin PB (July 2008). "Expression of the serpin centerin defines a germinal center phenotype in B-cell lymphomas". Am. J. Clin. Pathol. 130 (1): 117–26. doi:10.1309/9QKE68QU7B825A3U. PMID 18550480.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  104. ^ Huang X, Dementiev A, Olson ST, Gettins PG (April 2010). "Basis for the Specificity and Activation of the Serpin Protein Z-dependent Proteinase Inhibitor (ZPI) as an Inhibitor of Membrane-associated Factor Xa". J Biol Chem. 285 (26): 20399–409. doi:10.1074/jbc.M110.112748. PMC 2888451. PMID 20427285.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  105. ^ Huang X, Yan Y, Tu Y, et al. (July 2012). "Structural basis for catalytic activation of protein Z-dependent protease inhibitor (ZPI) by protein Z". Blood. 120 (8): 1726–33. doi:10.1182/blood-2012-03-419598. PMID 22786881.
  106. ^ Han X, Fiehler R, Broze GJ (2000). "Characterization of the protein Z-dependent protease inhibitor". Blood. 96 (9): 3049–55. PMID 11049983.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  107. ^ Corral J, Gonzalez-Conejero R, Soria JM, Gonzalez-Porras JR, Perez-Ceballos E, Lecumberri R, Roldan V, Souto JC, Minano A, Hernandez-Espinosa D, Alberca I, Fontcuberta J, Vicente V. (2006). "A nonsense polymorphism in the protein Z-dependent protease inhibitor increases the risk for venous thrombosis". Blood. 108 (1): 177–83. doi:10.1182/blood-2005-08-3249. PMC 1895831. PMID 16527896.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  108. ^ Heiker JT, Klöting N, Kovacs P, Kuettner EB, Sträter N, Schultz S, et al. (2013). "Vaspin inhibits kallikrein 7 by serpin mechanism". Cell Mol Life Sci. 70 (14): 2569–83. doi:10.1007/s00018-013-1258-8. PMID 23370777.
  109. ^ Hida K, Wada J, Eguchi J, Zhang H, Baba M, Seida A, Hashimoto I, Okada T, Yasuhara A, Nakatsuka A, Shikata K, Hourai S, Futami J, Watanabe E, Matsuki Y, Hiramatsu R, Akagi S, Makino H, Kanwar YS (2005 J). "Visceral adipose tissue-derived serine protease inhibitor: A unique insulin-sensitizing adipocytokine in obesity". Proc. Natl. Acad. Sci. U.S.A. 102 (30): 10610–5. doi:10.1073/pnas.0504703102. PMC 1180799. PMID 16030142. {{cite journal}}: Check date values in: |year= (help)CS1 maint: multiple names: authors list (link) CS1 maint: year (link)
  110. ^ Teshigawara S, Wada J, Hida K, et al. (July 2012). "Serum Vaspin Concentrations Are Closely Related to Insulin Resistance, and rs77060950 at SERPINA12 Genetically Defines Distinct Group with Higher Serum Levels in Japanese Population". J. Clin. Endocrinol. Metab. 97 (7): E1202–7. doi:10.1210/jc.2011-3297. PMID 22539588.
  111. ^ Baumann U, Bode W, Huber R, Travis J, Potempa J (August 1992). "Crystal structure of cleaved equine leucocyte elastase inhibitor determined at 1.95 A resolution". J. Mol. Biol. 226 (4): 1207–18. doi:10.1016/0022-2836(92)91062-T. PMID 1518052.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  112. ^ Remold-O'Donnell E, Chin J, Alberts M. (1992). "Sequence and molecular characterization of human monocyte/neutrophil elastase inhibitor". Proc. Natl. Acad. Sci. U.S.A. 89 (12): 5635–9. doi:10.1073/pnas.89.12.5635. PMC 49347. PMID 1376927.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  113. ^ Benarafa C, Priebe GP, Remold-O'donnell E. (2007). "The neutrophil serine protease inhibitor serpinb1 preserves lung defense functions in Pseudomonas aeruginosa infection". J. Exp. Med. 204 (8): 1901–9. doi:10.1084/jem.20070494. PMC 2118684. PMID 17664292.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  114. ^ Harrop SJ, Jankova L, Coles M, Jardine D, Whittaker JS, Gould AR, Meister A, King GC, Mabbutt BC, Curmi PM (January 1999). "The crystal structure of plasminogen activator inhibitor 2 at 2.0 A resolution: implications for serpin function". Structure. 7 (1): 43–54. doi:10.1016/S0969-2126(99)80008-2. PMID 10368272.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  115. ^ Antalis TM, La Linn M, Donnan K, Mateo L, Gardner J, Dickinson JL, Buttigieg K, Suhrbier A (1998). "The Serine Proteinase Inhibitor (Serpin) Plasminogen Activation Inhibitor Type 2 Protects against Viral Cytopathic Effects by Constitutive Interferon α/β Priming". J. Exp. Med. 187 (11): 1799–811. doi:10.1084/jem.187.11.1799. PMC 2212304. PMID 9607921.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  116. ^ Dougherty KM, Pearson JM, Yang AY, Westrick RJ, Baker MS, Ginsburg D. (1999). "The plasminogen activator inhibitor-2 gene is not required for normal murine development or survival". Proc. Natl. Acad. Sci. U.S.A. 96 (2): 686–91. doi:10.1073/pnas.96.2.686. PMC 15197. PMID 9892694.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  117. ^ Zhao A, Yang Z, Sun R, Grinchuk V, Netzel-Arnett S, Anglin IE, et al. (2013). "SerpinB2 is critical to Th2 immunity against enteric nematode infection". Journal of Immunology. 190 (11): 5779–87. doi:10.4049/jimmunol.1200293. PMID 23630350.
  118. ^ Zheng B, Matoba Y, Kumagai T, Katagiri C, Hibino T, Sugiyama M (February 2009). "Crystal structure of SCCA1 and insight about the interaction with JNK1". Biochem. Biophys. Res. Commun. 380 (1): 143–7. doi:10.1016/j.bbrc.2009.01.057. PMID 19166818.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  119. ^ a b Sivaprasad U, Askew DJ, Ericksen MB, et al. (January 2011). "A nonredundant role for mouse Serpinb3a in the induction of mucus production in asthma". The Journal of Allergy and Clinical Immunology. 127 (1): 254–61, 261.e1–6. doi:10.1016/j.jaci.2010.10.009. PMC 3058372. PMID 21126757.
  120. ^ Schick C, Kamachi Y, Bartuski AJ, Cataltepe S, Schechter NM, Pemberton PA, Silverman GA. (1997). "Squamous cell carcinoma antigen 2 is a novel serpin that inhibits the chymotrypsin-like proteinases cathepsin G and mast cell chymase". J Biol Chem. 272 (3): 1849–55. doi:10.1074/jbc.272.3.1849. PMID 8999871.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  121. ^ Law RH, Irving JA, Buckle AM, Ruzyla K, Buzza M, Bashtannyk-Puhalovich TA, Beddoe TC, Nguyen K, Worrall DM, Bottomley SP, Bird PI, Rossjohn J, Whisstock JC (June 2005). "The high resolution crystal structure of the human tumor suppressor maspin reveals a novel conformational switch in the G-helix". J. Biol. Chem. 280 (23): 22356–64. doi:10.1074/jbc.M412043200. PMID 15760906.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  122. ^ Teoh SS, Whisstock JC, Bird PI (April 2010). "Maspin (SERPINB5) Is an Obligate Intracellular Serpin". J. Biol. Chem. 285 (14): 10862–9. doi:10.1074/jbc.M109.073171. PMC 2856292. PMID 20123984.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  123. ^ Zou Z, Anisowicz A, Hendrix MJ, Thor A, Neveu M, Sheng S, Rafidi K, Seftor E, Sager R. (1994). "Maspin, a serpin with tumor-suppressing activity in human mammary epithelial cells". Science. 263 (5146): 526–9. doi:10.1126/science.8290962. PMID 8290962.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  124. ^ a b c Teoh, Sonia S. Y.; Vieusseux, Jessica; Prakash, Monica; Berkowicz, Susan; Luu, Jennii; Bird, Catherina H.; Law, Ruby H. P.; Rosado, Carlos; Price, John T.; Whisstock, James C.; Bird, Phillip I. (2014). "Maspin is not required for embryonic development or tumour suppression". Nature Communications. 5. doi:10.1038/ncomms4164. ISSN 2041-1723. PMC 3905777. PMID 24445777.
  125. ^ Gao F, Shi H, Daughty C, Cella N, Zhang M (2004). "Maspin plays an essential role in early embryonic development". Development. 131 (7): 1479–89. doi:10.1242/dev.01048. PMID 14985257.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  126. ^ Scott FL, Hirst CE, Sun J, Bird CH, Bottomley SP, Bird PI (1999). "The intracellular serpin proteinase inhibitor 6 is expressed in monocytes and granulocytes and is a potent inhibitor of the azurophilic granule protease, cathepsin G". Blood. 93 (6): 2089–97. PMID 10068683.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  127. ^ Scarff KL, Ung KS, Nandurkar H, Crack PJ, Bird CH, Bird PI. (2004). "Targeted Disruption of SPI3/Serpinb6 Does Not Result in Developmental or Growth Defects, Leukocyte Dysfunction, or Susceptibility to Stroke". Mol. Cell. Biol. 24 (9): 4075–82. doi:10.1128/MCB.24.9.4075-4082.2004. PMC 387772. PMID 15082799.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  128. ^ Sirmaci A, Erbek S, Price J, Huang M, Duman D, Cengiz FB, Bademci G, Tokgöz-Yilmaz S, Hişmi B, Ozdağ H, Oztürk B, Kulaksizoğlu S, Yildirim E, Kokotas H, Grigoriadou M, Petersen MB, Shahin H, Kanaan M, King MC, Chen ZY, Blanton SH, Liu XZ, Zuchner S, Akar N, Tekin M (May 2010). "A Truncating Mutation in SERPINB6 Is Associated with Autosomal-Recessive Nonsyndromic Sensorineural Hearing Loss". American Journal of Human Genetics. 86 (5): 797–804. doi:10.1016/j.ajhg.2010.04.004. PMC 2869020. PMID 20451170.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  129. ^ Tan J, Prakash MD, Kaiserman D, Bird PI (2013). "Absence of SERPINB6A causes sensorineural hearing loss with multiple histopathologies in the mouse inner ear". Am J Pathol. 183 (1): 49–59. doi:10.1016/j.ajpath.2013.03.009. PMID 23669344.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  130. ^ Miyata T, Inagi R, Nangaku M, Imasawa T, Sato M, Izuhara Y, Suzuki D, Yoshino A, Onogi H, Kimura M, Sugiyama S, Kurokawa K. (2002). "Overexpression of the serpin megsin induces progressive mesangial cell proliferation and expansion". J Clin Invest. 109 (5): 585–93. doi:10.1172/JCI14336. PMC 150894. PMID 11877466.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  131. ^ a b Miyata T, Li M, Yu X, Hirayama N (May 2007). "Megsin Gene: Its Genomic Analysis, Pathobiological Functions, and Therapeutic Perspectives". Curr. Genomics. 8 (3): 203–8. doi:10.2174/138920207780833856. PMC 2435355. PMID 18645605.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  132. ^ Kubo A, Shiohama A, Sasaki T, Nakabayashi K, Kawasaki H, Atsugi T, et al. (2013). "Mutations in SERPINB7, Encoding a Member of the Serine Protease Inhibitor Superfamily, Cause Nagashima-type Palmoplantar Keratosis". Am J Hum Genet. 93 (5): 945–56. doi:10.1016/j.ajhg.2013.09.015. PMC 3824127. PMID 24207119.
  133. ^ Yin J, Xu G, Wang H, Zhao J, Duo L, Cao X, et al. (2014). "New and Recurrent SERPINB7 Mutations in Seven Chinese Patients with Nagashima-type Palmoplantar Keratosis". J Invest Dermatol. 134 (8): 2269–72. doi:10.1038/jid.2014.80. PMID 24514002.
  134. ^ Dahlen JR, Jean F, Thomas G, Foster DC, Kisiel W (1998). "Inhibition of soluble recombinant furin by human proteinase inhibitor 8". J Biol Chem. 273 (4): 1851–4. doi:10.1074/jbc.273.4.1851. PMID 9442015.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  135. ^ Sun LD, Cheng H, Wang ZX, et al. (November 2010). "Association analyses identify six new psoriasis susceptibility loci in the Chinese population". Nat. Genet. 42 (11): 1005–9. doi:10.1038/ng.690. PMC 3140436. PMID 20953187.
  136. ^ Julià A, Tortosa R, Hernanz JM, et al. (July 2012). "Risk Variants for Psoriasis Vulgaris in a Large Case-Control Collection and Association with Clinical Subphenotypes". Hum Mol Genet. 21 (20): 4549–57. doi:10.1093/hmg/dds295. PMID 22814393.
  137. ^ Sun J, Bird CH, Sutton V, McDonald L, Coughlin PB, De Jong TA, Trapani JA, Bird PI (1996). "A cytosolic granzyme B inhibitor related to the viral apoptotic regulator cytokine response modifier A is present in cytotoxic lymphocytes". J. Biol. Chem. 271 (44): 27802–9. doi:10.1074/jbc.271.44.27802. PMID 8910377.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  138. ^ Zhang M, Park SM, Wang Y, Shah R, Liu N, Murmann AE, Wang CR, Peter ME, Ashton-Rickardt PG. (2006). "Serine protease inhibitor 6 protects cytotoxic T cells from self-inflicted injury by ensuring the integrity of cytotoxic granules". Immunity. 24 (4): 451–61. doi:10.1016/j.immuni.2006.02.002. PMID 16618603.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  139. ^ Rizzitelli A, Meuter S, Vega Ramos J, Bird CH, Mintern JD, Mangan MS, Villadangos J, Bird PI (July 2012). "Serpinb9 (Spi6)-deficient mice are impaired in dendritic cell-mediated antigen cross-presentation". Immunol Cell Biol. 90 (9): 841–51. doi:10.1038/icb.2012.29. PMID 22801574.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  140. ^ Riewald M, Chuang T, Neubauer A, Riess H, Schleef RR. (1998). "Expression of bomapin, a novel human serpin, in normal/malignant hematopoiesis and in the monocytic cell lines THP-1 and AML-193". Blood. 91 (4): 1256–62. PMID 9454755. Retrieved 6 January 2012.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  141. ^ a b Askew DJ, Cataltepe D, Kumar V, Edwards C, Pace SM, Howarth RN, Pak SC, Askew Y, Bromme D, Luke CJ, Whisstock JC, Silverman GA. (2007). "Serpinb11 is a new non-inhibitory intracellular serpin: Common single nucleotide polymorphisms in the scaffold impair conformational change". J. Biol. Chem. 282 (34): 24948–60. doi:10.1074/jbc.M703182200. PMID 17562709.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  142. ^ Finno CJ, Stevens C, Young A, Affolter V, Joshi NA, Ramsay S, Bannasch DL (2015). "SERPINB11 Frameshift Variant Associated with Novel Hoof Specific Phenotype in Connemara Ponies". PLoS Genet. 11 (4): e1005122. doi:10.1371/journal.pgen.1005122. PMID 25875171.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  143. ^ Askew YS, Pak SC, Luke CJ, Askew DJ, Cataltepe S, Mills DR, Kato H, Lehoczky J, Dewar K, Birren B, Silverman GA. (2001). "SERPINB12 is a novel member of the human ov-serpin family that is widely expressed and inhibits trypsin-like serine proteinases". J. Biol. Chem. 276 (52): 49320–30. doi:10.1074/jbc.M108879200. PMID 11604408.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  144. ^ Welss T, Sun J, Irving JA, Blum R, Smith AI, Whisstock JC, Pike RN, von Mikecz A, Ruzicka T, Bird PI, Abts HF. (2003). "Hurpin is a selective inhibitor of lysosomal cathepsin L and protects keratinocytes from ultraviolet-induced apoptosis". Biochemistry. 42 (24): 7381–9. doi:10.1021/bi027307q. PMID 12809493.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  145. ^ Huntington JA (2006). "Shape-shifting serpins--advantages of a mobile mechanism". Trends Biochem. Sci. 31 (8): 427–35. doi:10.1016/j.tibs.2006.06.005. PMID 16820297.
  146. ^ Bruce D, Perry DJ, Borg JY, Carrell RW, Wardell MR. (1994). "Thromboembolic disease due to thermolabile conformational changes of antithrombin Rouen-VI (187 Asn-->Asp)". J. Clin. Invest. 94 (6): 2265–74. doi:10.1172/JCI117589. PMC 330053. PMID 7989582.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  147. ^ Baglin TP, Carrell RW, Church FC, Esmon CT, Huntington JA (2002). "Crystal structures of native and thrombin-complexed heparin cofactor II reveal a multistep allosteric mechanism". Proc. Natl. Acad. Sci. U.S.A. 99 (17): 11079–84. doi:10.1073/pnas.162232399. PMC 123213. PMID 12169660.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  148. ^ Vicente CP, He L, Pavao MS, Tollefsen DM (2004). "Antithrombotic activity of dermatan sulfate in heparin cofactor II-deficient mice". Blood. 104 (13): 3965–70. doi:10.1182/blood-2004-02-0598. PMID 15315969.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  149. ^ Aihara K, Azuma H, Akaike M, Ikeda Y, Sata M, Takamori N, Yagi S, Iwase T, Sumitomo Y, Kawano H, Yamada T, Fukuda T, Matsumoto T, Sekine K, Sato T, Nakamichi Y, Yamamoto Y, Yoshimura K, Watanabe T, Nakamura T, Oomizu A, Tsukada M, Hayashi H, Sudo T, Kato S, Matsumoto T. (2007). "Strain-dependent embryonic lethality and exaggerated vascular remodeling in heparin cofactor II–deficient mice". J. Clin. Invest. 117 (6): 1514–26. doi:10.1172/JCI27095. PMC 1878511. PMID 17549254.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  150. ^ Stout TJ, Graham H, Buckley DI, Matthews DJ (July 2000). "Structures of active and latent PAI-1: a possible stabilizing role for chloride ions". Biochemistry. 39 (29): 8460–9. doi:10.1021/bi000290w. PMID 10913251.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  151. ^ Zhou A, Huntington JA, Pannu NS, Carrell RW, Read RJ (July 2003). "How vitronectin binds PAI-1 to modulate fibrinolysis and cell migration". Nature Structural & Molecular Biology. 10 (7): 541–4. doi:10.1038/nsb943. PMID 12808446.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  152. ^ Cale JM, Lawrence DA (2007). "Structure-function relationships of plasminogen activator inhibitor-1 and its potential as a therapeutic agent". Curr. Drug Targets. 8 (9): 971–81. doi:10.2174/138945007781662337. PMID 17896949.
  153. ^ Gils A, Declerck PJ. (2004). "The structural basis for the pathophysiological relevance of PAI-I in cardiovascular diseases and the development of potential PAI-I inhibitors". Thromb. Haemost. 91 (3): 425–37. doi:10.1160/TH03-12-0764. PMID 14983217.
  154. ^ Bajou K, Peng H, Laug WE, et al. (October 2008). "Plasminogen Activator Inhibitor-1 Protects Endothelial Cells from FasL-Mediated Apoptosis". Cancer Cell. 14 (4): 324–34. doi:10.1016/j.ccr.2008.08.012. PMC 2630529. PMID 18835034.
  155. ^ Li W, Huntington JA (May 2012). "Crystal structures of protease nexin-1 in complex with heparin and thrombin suggest a two-step recognition mechanism". Blood. 120 (2): 459–67. doi:10.1182/blood-2012-03-415869. PMID 22618708.
  156. ^ Lino MM, Atanasoski S, Kvajo M, Fayard B, Moreno E, Brenner HR, Suter U, Monard D (2007). "Mice lacking protease nexin-1 show delayed structural and functional recovery after sciatic nerve crush". J. Neurosci. 27 (14): 3677–85. doi:10.1523/JNEUROSCI.0277-07.2007. PMID 17409231.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  157. ^ Murer V, Spetz JF, Hengst U, Altrogge LM, de Agostini A, Monard D. (2001). "Male fertility defects in mice lacking the serine protease inhibitor protease nexin-1". Proc. Natl. Acad. Sci. U.S.A. 98 (6): 3029–33. doi:10.1073/pnas.051630698. PMC 30601. PMID 11248026.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  158. ^ Lüthi A, Van der Putten H, Botteri FM, Mansuy IM, Meins M, Frey U, Sansig G, Portet C, Schmutz M, Schröder M, Nitsch C, Laurent JP, Monard D (1997). "Endogenous serine protease inhibitor modulates epileptic activity and hippocampal long-term potentiation". J. Neurosci. 17 (12): 4688–99. PMID 9169529.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  159. ^ Simonovic M, Gettins PG, Volz K (September 2001). "Crystal structure of human PEDF, a potent anti-angiogenic and neurite growth-promoting factor". Proc. Natl. Acad. Sci. U.S.A. 98 (20): 11131–5. doi:10.1073/pnas.211268598. PMC 58695. PMID 11562499.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  160. ^ a b Doll JA, Stellmach VM, Bouck NP, Bergh AR, Lee C, Abramson LP, Cornwell ML, Pins MR, Borensztajn J, Crawford SE. (2003). "Pigment epithelium-derived factor regulates the vasculature and mass of the prostate and pancreas". Nat. Med. 9 (6): 774–80. doi:10.1038/nm870. PMID 12740569.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  161. ^ Becerra SP, Perez-Mediavilla LA, Weldon JE, et al. (September 2008). "Pigment Epithelium-derived Factor Binds to Hyaluronan: MAPPING OF A HYALURONAN BINDING SITE". The Journal of Biological Chemistry. 283 (48): 33310–20. doi:10.1074/jbc.M801287200. PMC 2586245. PMID 18805795.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  162. ^ Andreu-Agulló, C.; Morante-Redolat, J. � M.; Delgado, A. C.; Fariñas, I. (2009). "Vascular niche factor PEDF modulates Notch-dependent stemness in the adult subependymal zone". Nature Neuroscience. 12 (12): 1514–1523. doi:10.1038/nn.2437. PMID 19898467. {{cite journal}}: replacement character in |first2= at position 4 (help)
  163. ^ Law RH, Sofian T, Kan WT, Horvath AJ, Hitchen CR, Langendorf CG, Buckle AM, Whisstock JC, Coughlin PB (2008). "The X-ray crystal structure of the fibrinolysis inhibitor {alpha}2-antiplasmin". Blood. 111 (4): 2049–2052. doi:10.1182/blood-2007-09-114215. PMID 18063751.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  164. ^ Wiman B, Collen D (1979). "On the mechanism of the reaction between human alpha 2-antiplasmin and plasmin". J. Biol. Chem. 254 (18): 9291–7. PMID 158022.
  165. ^ Miles LA, Plow EF, Donnelly KJ, Hougie C, Griffin JH. (1982). "A bleeding disorder due to deficiency of alpha 2-antiplasmin". Blood. 59 (6): 1246–51. PMID 7082827.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  166. ^ a b Beinrohr L, Harmat V, Dobo J, Lorincz Z, Gal P, Zavodszky P. (2007). "C1-inhibitor serpin domain structure reveals the likely mechanism of heparin potentiation and conformational disease". J Biol Chem. 282 (29): 21100–9. doi:10.1074/jbc.M700841200. PMID 17488724.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  167. ^ Aulak KS, Eldering E, Hack CE, Lubbers YP, Harrison RA, Mast A, Cicardi M, Davis AE 3rd. (1993). "A hinge region mutation in C1-inhibitor (Ala436-->Thr) results in nonsubstrate-like behavior and in polymerization of the molecule". J. Biol. Chem. 268 (24): 18088–94. PMID 8349686.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: numeric names: authors list (link)
  168. ^ Ennis S, Jomary C, Mullins R, et al. (October 2008). "Association between the SERPING1 gene and age-related macular degeneration: a two-stage case-control study". Lancet. 372 (9652): 1828–34. doi:10.1016/S0140-6736(08)61348-3. PMID 18842294.
  169. ^ Widmer C, Gebauer JM, Brunstein E, et al. (July 2012). "Molecular basis for the action of the collagen-specific chaperone Hsp47/SERPINH1 and its structure-specific client recognition". Proc. Natl. Acad. Sci. U.S.A. 109 (33): 13243–7. doi:10.1073/pnas.1208072109. PMC 3421173. PMID 22847422.
  170. ^ Hirayoshi K, Kudo H, Takechi H, Nakai A, Iwamatsu A, Yamada KM, Nagata K (1991). "HSP47: a tissue-specific, transformation-sensitive, collagen-binding heat shock protein of chicken embryo fibroblasts". Mol. Cell. Biol. 11 (8): 4036–44. PMC 361208. PMID 2072906.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  171. ^ Nagai N, Hosokawa M, Itohara S, Adachi E, Matsushita T, Hosokawa N, Nagata K (2000). "Embryonic Lethality of Molecular Chaperone Hsp47 Knockout Mice Is Associated with Defects in Collagen Biosynthesis". J Cell Biol. 150 (6): 1499–506. doi:10.1083/jcb.150.6.1499. PMC 2150697. PMID 10995453.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  172. ^ Christiansen HE, Schwarze U, Pyott SM, AlSwaid A, Al Balwi M, Alrasheed S, Pepin MG, Weis MA, Eyre DR, Byers PH (March 2010). "Homozygosity for a Missense Mutation in SERPINH1, which Encodes the Collagen Chaperone Protein HSP47, Results in Severe Recessive Osteogenesis Imperfecta". American Journal of Human Genetics. 86 (3): 389–98. doi:10.1016/j.ajhg.2010.01.034. PMC 2833387. PMID 20188343.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  173. ^ Drögemüller C, Becker D, Brunner A, et al. (July 2009). "A missense mutation in the SERPINH1 gene in Dachshunds with osteogenesis imperfecta". PLOS Genetics. 5 (7): e1000579. doi:10.1371/journal.pgen.1000579. PMC 2708911. PMID 19629171.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  174. ^ Takehara S, Onda M, Zhang J, Nishiyama M, Yang X, Mikami B, Lomas DA (March 2009). "2.1A Crystal Structure of Native Neuroserpin Reveals Unique Structural Elements that Contribute to Conformational Instability". J. Mol. Biol. 388 (1): 11–20. doi:10.1016/j.jmb.2009.03.007. PMID 19285087.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  175. ^ Ricagno S, Caccia S, Sorrentino G, Antonini G, Bolognesi M (March 2009). "Human Neuroserpin; Structure and Time-dependent Inhibition". J. Mol. Biol. 388 (1): 109–21. doi:10.1016/j.jmb.2009.02.056. PMID 19265707.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  176. ^ Osterwalder T, Cinelli P, Baici A, Pennella A, Krueger SR, Schrimpf SP, Meins M, Sonderegger P (1998). "The axonally secreted serine proteinase inhibitor, neuroserpin, inhibits plasminogen activators and plasmin but not thrombin". J. Biol. Chem. 273 (4): 2312–21. doi:10.1074/jbc.273.4.2312. PMID 9442076.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  177. ^ Davis RL, Shrimpton AE, Holohan PD, Bradshaw C, Feiglin D, Collins GH, Sonderegger P, Kinter J, Becker LM, Lacbawan F, Krasnewich D, Muenke M, Lawrence DA, Yerby MS, Shaw CM, Gooptu B, Elliott PR, Finch JT, Carrell RW, Lomas DA. (1999). "Familial dementia caused by polymerization of mutant neuroserpin". Nature. 401 (6751): 376–9. doi:10.1038/43894. PMID 10517635.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  178. ^ a b Ozaki K, Nagata M, Suzuki M, Fujiwara T, Miyoshi Y, Ishikawa O, Ohigashi H, Imaoka S, Takahashi E, Nakamura Y. (1998). "Isolation and characterization of a novel human pancreas-specific gene, pancpin, that is down-regulated in pancreatic cancer cells". Genes Chromosomes and Cancer. 22 (3): 179–85. doi:10.1002/(SICI)1098-2264(199807)22:3<179::AID-GCC3>3.0.CO;2-T. PMID 9624529.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  179. ^ Loftus SK, Cannons JL, Incao A, Pak E, Chen A, Zerfas PM, Bryant MA, Biesecker LG, Schwartzberg PL, Pavan WJ (2005). "Acinar Cell Apoptosis in Serpini2-Deficient Mice Models Pancreatic Insufficiency". PLoS. Genet. 1 (3): e38. doi:10.1371/journal.pgen.0010038. PMC 1231717. PMID 16184191.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  180. ^ Padua MB, Kowalski AA, Cañas MY, Hansen PJ (February 2010). "The molecular phylogeny of uterine serpins and its relationship to evolution of placentation". FASEB J. 24 (2): 526–37. doi:10.1096/fj.09-138453. PMID 19825977.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  181. ^ Padua MB, Hansen PJ (October 2010). "Evolution and function of the uterine serpins (SERPINA14)". Am. J. Reprod. Immunol. 64 (4): 265–74. doi:10.1111/j.1600-0897.2010.00901.x. PMID 20678169.
  182. ^ a b Reichhart JM. (2005). "Tip of another iceberg: Drosophila serpins". Trends Cell Biol. 15 (12): 659–665. doi:10.1016/j.tcb.2005.10.001. PMID 16260136.
  183. ^ Tang H, Kambris Z, Lemaitre B, Hashimoto C (October 2008). "A SERPIN THAT REGULATES IMMUNE MELANIZATION IN THE RESPIRATORY SYSTEM OF DROSOPHILA". Developmental cell. 15 (4): 617–26. doi:10.1016/j.devcel.2008.08.017. PMC 2671232. PMID 18854145.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  184. ^ Scherfer C, Tang H, Kambris Z, Lhocine N, Hashimoto C, Lemaitre B (September 2008). "Drosophila Serpin-28D regulates hemolymph phenoloxidase activity and adult pigmentation". Developmental biology. 323 (2): 189–96. doi:10.1016/j.ydbio.2008.08.030. PMID 18801354.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  185. ^ Rushlow C (2004). "Dorsoventral patterning: a serpin pinned down at last". Curr. Biol. 14 (1): R16–8. doi:10.1016/j.cub.2003.12.015. PMID 14711428.
  186. ^ Ligoxygakis P, Roth S, Reichhart JM (2003). "A serpin regulates dorsal-ventral axis formation in the Drosophila embryo". Curr. Biol. 13 (23): 2097–102. doi:10.1016/j.cub.2003.10.062. PMID 14654000.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  187. ^ Hashimoto C, Kim DR, Weiss LA, Miller JW, Morisato D (2003). "Spatial regulation of developmental signaling by a serpin". Dev. Cell. 5 (6): 945–50. doi:10.1016/S1534-5807(03)00338-1. PMID 14667416.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  188. ^ Jiang R, Zhang B, Kurokawa K, et al. (August 2011). "93-kDa Twin-domain Serine Protease Inhibitor (Serpin) Has a Regulatory Function on the Beetle Toll Proteolytic Signaling Cascade". J Biol Chem. 286 (40): 35087–95. doi:10.1074/jbc.M111.277343. PMC 3186399. PMID 21862574.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  189. ^ Cliff J. Luke, Stephen C. Pak, Yuko S. Askew, Terra L. Naviglia, David J. Askew, Shila M. Nobar, Anne C. Vetica, Olivia S. Long, Simon C. Watkins, Donna B. Stolz, Robert J. Barstead, Gary L. Moulder, Dieter Brömme, and Gary A. Silverman (2007). "An Intracellular Serpin Regulates Necrosis by Inhibiting the Induction and Sequelae of Lysosomal Injury". Cell. 130 (6): 1108–1119. doi:10.1016/j.cell.2007.07.013. PMC 2128786. PMID 17889653.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  190. ^ Hejgaard J, Rasmussen SK, Brandt A, SvendsenI (1985). "Sequence homology between barley endosperm protein Z and protease inhibitors of the alpha-1-antitrypsin family". FEBS Lett. 180 (1): 89–94. doi:10.1016/0014-5793(85)80238-6.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  191. ^ Dahl SW, Rasmussen SK, Peterson LC, Hejgaard J. (1996). "Inhibition of coagulation factors by recombinant barley serpin BSZx". FEBS Lett. 394 (2): 165–8. doi:10.1016/0014-5793(96)00940-4. PMID 8843156.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  192. ^ Hejgaard J. (2001). "Inhibitory serpins from rye grain with glutamine as P1 and P2 residues in the reactive center". FEBS Lett. 488 (3): 149–53. doi:10.1016/S0014-5793(00)02425-X. PMID 11163762.
  193. ^ Ostergaard H, Rasmussen SK, Roberts TH, Hejgaard J. (2000). "Inhibitory serpins from wheat grain with reactive centers resembling glutamine-rich repeats of prolamin storage proteins. Cloning and characterization of five major molecular forms". J Biol Chem. 275 (43): 33272–9. doi:10.1074/jbc.M004633200. PMID 10874043.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  194. ^ a b Yoo BC, Aoki K, Xiang Y, Campbell LR, Hull RJ, Xoconostle-Cázares B, Monzer J, Lee JY, Ullman DE, Lucas WJ. (2000). "Characterization of cucurbita maxima phloem serpin-1 (CmPS-1). A developmentally regulated elastase inhibitor". J Biol Chem. 275 (45): 35122–8. doi:10.1074/jbc.M006060200. PMID 10960478.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  195. ^ la Cour Petersen M, Hejgaard J, Thompson GA, Schulz A. (2005). "Cucurbit phloem serpins are graft-transmissible and appear to be resistant to turnover in the sieve element-companion cell complex". J Exp Bot. 56 (422): 3111–20. doi:10.1093/jxb/eri308. PMID 16246856.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  196. ^ Roberts TH, Hejgaard J. (2008). "Serpins in plants and green algae". Funct Integr Genomics. 8 (1): 1–27. doi:10.1007/s10142-007-0059-2. PMID 18060440.
  197. ^ Lampl N, Alkan N, Davydov O, Fluhr R (2013). "Set-point control of RD21 protease activity by AtSerpin1 controls cell death in Arabidopsis". Plant J. 74 (3): 498–510. doi:10.1111/tpj.12141. PMID 23398119.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  198. ^ Ahn J-W, Atwell BJ, Roberts TH. (2009). "Serpin genes AtSRP2 and AtSRP3 are required for normal growth sensitivity to a DNA alkylating agent in Arabidopsis". BMC Plant Biol. 9: 52. doi:10.1186/1471-2229-9-52. PMC 2689219. PMID 19426562. {{cite journal}}: |article= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  199. ^ a b Kang S, Barak Y, Lamed R, Bayer EA, Morrison M. (2006). "The functional repertoire of prokaryote cellulosomes includes the serpin superfamily of serine proteinase inhibitors". Mol Microbiol. 60 (6): 1344–54. doi:10.1111/j.1365-2958.2006.05182.x. PMID 16796673.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  200. ^ Irving JA, Cabrita LD, Rossjohn J, Pike RN, Bottomley SP, Whisstock JC (2003). "The 1.5 A crystal structure of a prokaryote serpin: controlling conformational change in a heated environment". Structure. 11 (4): 387–97. doi:10.1016/S0969-2126(03)00057-1. PMID 12679017.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  201. ^ Fulton KF, Buckle AM, Cabrita LD, Irving JA, Butcher RE, Smith I, Reeve S, Lesk AM, Bottomley SP, Rossjohn J, Whisstock JC. (2005). "The high resolution crystal structure of a native thermostable serpin reveals the complex mechanism underpinning the stressed to relaxed transition". J Biol Chem. 280 (9): 8435–42. doi:10.1074/jbc.M410206200. PMID 15590653.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  202. ^ Turner PC, Moyer RW (2002). "Poxvirus immune modulators: functional insights from animal models". Virus Res. 88 (1–2): 35–53. doi:10.1016/S0168-1702(02)00119-3. PMID 12297326.
  203. ^ a b Richardson J, Viswanathan K, Lucas A (2006). "Serpins, the vasculature, and viral therapeutics". Front. Biosci. 11: 1042–56. doi:10.2741/1862. PMID 16146796.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  204. ^ Jiang J, Arp J, Kubelik D, Zassoko R, Liu W, Wise Y, Macaulay C, Garcia B, McFadden G, Lucas AR, Wang H (2007). "Induction of indefinite cardiac allograft survival correlates with toll-like receptor 2 and 4 downregulation after serine protease inhibitor-1 (Serp-1) treatment". Transplantation. 84 (9): 1158–67. doi:10.1097/01.tp.0000286099.50532.b0. PMID 17998872. {{cite journal}}: Unknown parameter |subscription= ignored (|url-access= suggested) (help)CS1 maint: multiple names: authors list (link)
  205. ^ Dai E, Guan H, Liu L, Little S, McFadden G, Vaziri S, Cao H, Ivanova IA, Bocksch L, Lucas A (2003). "Serp-1, a viral anti-inflammatory serpin, regulates cellular serine proteinase and serpin responses to vascular injury". J. Biol. Chem. 278 (20): 18563–72. doi:10.1074/jbc.M209683200. PMID 12637546.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  206. ^ Turner PC, Sancho MC, Thoennes SR, Caputo A, Bleackley RC, Moyer RW (1999). "Myxoma Virus Serp2 Is a Weak Inhibitor of Granzyme B and Interleukin-1β-Converting Enzyme In Vitro and Unlike CrmA Cannot Block Apoptosis in Cowpox Virus-Infected Cells". J. Virol. 73 (8): 6394–404. PMC 112719. PMID 10400732.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  207. ^ Munuswamy-Ramanujam G, Khan KA, Lucas AR (2006). "Viral anti-inflammatory reagents: the potential for treatment of arthritic and vasculitic disorders". Endocr Metab Immune Disord Drug Targets. 6 (4): 331–43. doi:10.2174/187153006779025720. PMID 17214579.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  208. ^ Renatus M, Zhou Q, Stennicke HR, Snipas SJ, Turk D, Bankston LA, Liddington RC, Salvesen GS (2000). "Crystal structure of the apoptotic suppressor CrmA in its cleaved form". Structure. 8 (7): 789–97. doi:10.1016/S0969-2126(00)00165-9. PMID 10903953.{{cite journal}}: CS1 maint: multiple names: authors list (link)

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