Apolipoprotein H

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Apolipoprotein H (beta-2-glycoprotein I)
Apolipoprotein-H.png
Derived from PDB structure 1C1Z. Blue regions are positively charged and red regions are negatively charged.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols APOH ; B2G1; B2GP1; BG
External IDs OMIM138700 MGI88058 HomoloGene26 ChEMBL: 2859 GeneCards: APOH Gene
RNA expression pattern
PBB GE APOH 205216 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 350 11818
Ensembl ENSG00000091583 ENSMUSG00000000049
UniProt P02749 Q01339
RefSeq (mRNA) NM_000042 NM_013475
RefSeq (protein) NP_000033 NP_038503
Location (UCSC) Chr 17:
64.21 – 64.25 Mb
Chr 11:
108.34 – 108.41 Mb
PubMed search [1] [2]

Apolipoprotein H (Apo-H), previously known as (β2-glycoprotein I, beta-2 glycoprotein I), is a multifunctional apolipoprotein. One of its functions is to bind cardiolipin. When bound the structure of cardiolipin and Apo-H both undergo large changes in structure.[1] Within the structure of Apo-H is a stretch of positively charged amino acids, (protein sequence positions 282-287) Lys-Asn-Lys-Glu-Lys-Lys, are involved in phospholipid binding (See image on right).[2]

Apo-H has a complex involvement in agglutination, it appears to alter ADP mediated agglutination of platelets.[3] Normally Apo-H assumes an anti-coagulation activity in serum (by inhibiting coagulation factors), however changes in blood factors can result of a reversal of that activity.

Inhibitory activities[edit]

Apo-H appears to completely inhibit serotonin release by the platelets[4] and prevents subsequent waves of the ADP-induced aggregation. The activity of Apo-H appears to involve the binding of agglutinating, negatively charged compounds, and inhibits agglutination by the contact activation of the intrinsic blood coagulation pathway.[5] Apo-H causes a reduction of the prothrombinase binding sites on platelets and reduces the activation caused by collagen when thrombin is present at physiological serum concentrations of Apo-H suggesting a regulatory role of Apo-H in coagulation.[6]

Apo-H also inhibits the generation of factor Xa in the presence of platelets.[7] Apo-H also inhibits that activation of factor XIIa.[8]

In addition, Apo-H inhibits the activation of protein C blocking its activity on phosphatidylserine:phosphatidylcholine vesicles[9] however once protein C is activated, Apo-H fails to inhibit activity. Since protein C is involved in factor Va degradation Apo-H indirectly inhibits the degradation of factor Va.[10] This inhibitory activity was diminished by adding phospholipids suggesting the Apo-H inhibition of protein C is phospholipid competitive.[11] This indicates that under certain conditions Apo-H takes on a procoagulation properties.

Pathology[edit]

Anti-cardiolipin antibodies are found in both infectious (syphilis) and autoimmune disease (sclerosis, lupus).[12] The activity of anti-cardiolipin antibodies in autoimmune antiphospholipid syndrome requires apolipoprotein H.[13][14] The subset of antibodies that bind Apo-H and alter its activity are considered different from antibodies that bind thrombin, serum phospholipids and are called anti-apolipoprotein antibodies. In autoimmune disease, anti-apolipoprotein antibodies (Anti β2 glycoprotein I antibodies) strongly associate with thrombotic forms of lupus and sclerosis.

Sushi 2 protein domain[edit]

Sushi_2
PDB 1g4g EBI.jpg
NMR structure of the fifth domain of human beta-2-glycoprotein I
Identifiers
Symbol Sushi_2
Pfam PF09014
InterPro IPR015104

In molecular biology, the protein domain Sushi 2 is also known as the fifth protein domain of beta-2-glycoprotein-1 (b2GP-1). This protein domain is only found in eukaryotes. The first four domains found in Apolipoprotein H resemble each other, however the fifth one appears to be different.[15]

Structure[edit]

This protein domain is composed of four well-defined anti-parallel beta-strands and two short alpha-helices, as well as a long highly flexible loop.[16] Additionally, the fifth protein domain appears to resemble the other four in Apolipoprotein with the exception of three internal disulfide bonds and an extra C-terminal loop.[15]

Function[edit]

Its exact function remains to be fully elucidated, however it is known to play an important role in the binding of b2GP-1 to negatively charged compounds and subsequent capture for binding of anti-b2GP-1 antibodies.[16] Problems such as a mutation in this protein would lead to Antiphospholipid syndrome which often leads to pregnancy complications.[15]

References[edit]

  1. ^ Borchman D, Harris EN, Pierangeli SS, Lamba OP (1995). "Interactions and molecular structure of cardiolipin and beta 2-glycoprotein 1 (beta 2-GP1)". Clin. Exp. Immunol. 102 (2): 373–8. doi:10.1111/j.1365-2249.1995.tb03792.x. PMC 1553418. PMID 7586693. 
  2. ^ Sheng Y, Sali A, Herzog H, Lahnstein J, Krilis SA (1996). "Site-directed mutagenesis of recombinant human beta 2-glycoprotein I identifies a cluster of lysine residues that are critical for phospholipid binding and anti-cardiolipin antibody activity". J. Immunol. 157 (8): 3744–51. PMID 8871678. 
  3. ^ Nimpf J, Wurm H, Kostner GM (1985). "Interaction of beta 2-glycoprotein-I with human blood platelets: influence upon the ADP-induced aggregation". Thromb. Haemost. 54 (2): 397–401. PMID 4082080. 
  4. ^ Nimpf J, Wurm H, Kostner GM (1987). "Beta 2-glycoprotein-I (apo-H) inhibits the release reaction of human platelets during ADP-induced aggregation". Atherosclerosis 63 (2–3): 109–14. doi:10.1016/0021-9150(87)90110-9. PMID 3827975. 
  5. ^ Schousboe I (1985). "beta 2-Glycoprotein I: a plasma inhibitor of the contact activation of the intrinsic blood coagulation pathway". Blood 66 (5): 1086–91. PMID 4052628. 
  6. ^ Nimpf J, Bevers EM, Bomans PH, et al. (1986). "Prothrombinase activity of human platelets is inhibited by beta 2-glycoprotein-I". Biochim. Biophys. Acta 884 (1): 142–9. doi:10.1016/0304-4165(86)90237-0. PMID 3768409. 
  7. ^ Shi W, Chong BH, Hogg PJ, Chesterman CN (1993). "Anticardiolipin antibodies block the inhibition by beta 2-glycoprotein I of the factor Xa generating activity of platelets". Thromb. Haemost. 70 (2): 342–5. PMID 8236146. 
  8. ^ Schousboe I, Rasmussen MS (1995). "Synchronized inhibition of the phospholipid mediated autoactivation of factor XII in plasma by beta 2-glycoprotein I and anti-beta 2-glycoprotein I". Thromb. Haemost. 73 (5): 798–804. PMID 7482406. 
  9. ^ Keeling DM, Wilson AJ, Mackie IJ, Isenberg DA, Machin SJ (1993). "Role of beta 2-glycoprotein I and anti-phospholipid antibodies in activation of protein C in vitro". J. Clin. Pathol. 46 (10): 908–11. doi:10.1136/jcp.46.10.908. PMC 501616. PMID 8227406. 
  10. ^ Matsuda J, Gohchi K, Kawasugi K, Gotoh M, Saitoh N, Tsukamoto M (1995). "Inhibitory activity of anti-beta 2-glycoprotein I antibody on factor Va degradation by activated-protein C and its cofactor protein S". Am. J. Hematol. 49 (1): 89–91. doi:10.1002/ajh.2830490116. PMID 7741146. 
  11. ^ Mori T, Takeya H, Nishioka J, Gabazza EC, Suzuki K (1996). "beta 2-Glycoprotein I modulates the anticoagulant activity of activated protein C on the phospholipid surface". Thromb. Haemost. 75 (1): 49–55. PMID 8713779. 
  12. ^ Kumar KS, Jyothy A, Prakash MS, Rani HS, Reddy PP (2002). "Beta2-glycoprotein I dependent anticardiolipin antibodies and lupus anticoagulant in patients with recurrent pregnancy loss". Journal of postgraduate medicine 48 (1): 5–10. PMID 12082318. 
  13. ^ McNeil HP, Simpson RJ, Chesterman CN, Krilis SA (1990). "Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein I (apolipoprotein H)". Proc. Natl. Acad. Sci. U.S.A. 87 (11): 4120–4. doi:10.1073/pnas.87.11.4120. PMC 54059. PMID 2349221. 
  14. ^ Hunt JE, McNeil HP, Morgan GJ, Crameri RM, Krilis SA (1992). "A phospholipid-beta 2-glycoprotein I complex is an antigen for anticardiolipin antibodies occurring in autoimmune disease but not with infection". Lupus 1 (2): 75–81. doi:10.1177/096120339200100204. PMID 1301967. 
  15. ^ a b c Shi T, Giannakopoulos B, Iverson GM, Cockerill KA, Linnik MD, Krilis SA (2005). "Domain V of beta2-glycoprotein I binds factor XI/XIa and is cleaved at Lys317-Thr318.". J Biol Chem 280 (2): 907–12. doi:10.1074/jbc.M410291200. PMID 15522884. 
  16. ^ a b Hoshino M, Hagihara Y, Nishii I, Yamazaki T, Kato H, Goto Y (December 2000). "Identification of the phospholipid-binding site of human beta(2)-glycoprotein I domain V by heteronuclear magnetic resonance". J. Mol. Biol. 304 (5): 927–39. doi:10.1006/jmbi.2000.4243. PMID 11124037. 

External links[edit]