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{{distinguish|Laminins}}
{{distinguish|Laminins}}
'''Nuclear lamins''', also known as Class V [[intermediate filaments]], are [[fibrous protein]]s providing structural function and [[Transcription (genetics)|transcriptional]] regulation in the [[cell nucleus]]. Nuclear lamins interact with membrane-associated proteins to form the [[nuclear lamina]] on the interior of the nuclear envelope. Lamins are present in all members of the kingdom Animalia (Metazoa), but are not found in unicellular organisms, plants, or fungi<ref>{{Cite journal|last=Dechat|first=Thomas|last2=Adam|first2=Stephen A.|last3=Taimen|first3=Pekka|last4=Shimi|first4=Takeshi|last5=Goldman|first5=Robert D.|date=2016-11-24|title=Nuclear Lamins|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964183/|journal=Cold Spring Harbor Perspectives in Biology|volume=2|issue=11|doi=10.1101/cshperspect.a000547|issn=1943-0264|pmc=2964183|pmid=20826548}}</ref><ref>{{Cite book|title=Becker's World of the Cell, 9th Edition|last=Hardin Jeff|first=and Bertoni Gregory|publisher=Pearson|year=2016|isbn=9780321934925|location=Boston, MA|pages=|quote=|via=}}</ref>. Lamin proteins are involved in the disassembling and reforming of the nuclear envelope during [[mitosis]], the positioning of [[nuclear pore|nuclear pores,]] and [[programmed cell death]]. Mutations in lamin genes can result in [[laminopathies]], some of which are potentially lethal disorders.
'''Nuclear lamins''', also known as Class V [[intermediate filaments]], are [[fibrous protein]]s providing structural function and [[Transcription (genetics)|transcriptional]] regulation in the [[cell nucleus]]. Nuclear lamins interact with membrane-associated proteins to form the [[nuclear lamina]] on the interior of the nuclear envelope. Lamins are present in all members of the kingdom Animalia (Metazoa), but are not found in unicellular organisms, plants, or fungi<ref name=":0">{{Cite journal|last=Dechat|first=Thomas|last2=Adam|first2=Stephen A.|last3=Taimen|first3=Pekka|last4=Shimi|first4=Takeshi|last5=Goldman|first5=Robert D.|date=2016-11-24|title=Nuclear Lamins|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964183/|journal=Cold Spring Harbor Perspectives in Biology|volume=2|issue=11|doi=10.1101/cshperspect.a000547|issn=1943-0264|pmc=2964183|pmid=20826548}}</ref><ref name=":1">{{Cite book|title=Becker's World of the Cell, 9th Edition|last=Hardin Jeff|first=and Bertoni Gregory|publisher=Pearson|year=2016|isbn=9780321934925|location=Boston, MA|pages=|quote=|via=}}</ref>. Lamin proteins are involved in the disassembling and reforming of the nuclear envelope during [[mitosis]], the positioning of [[nuclear pore|nuclear pores,]] and [[programmed cell death]]. Mutations in lamin genes can result in [[laminopathies]], some of which are potentially lethal disorders.

== Brief History of Lamins ==
Nuclear lamins were first identified using [[Electron microscope|electron-microscopy]]. However, they were not recognized as vital components of nuclear structural support until 1975<ref name=":2">{{Cite journal|last=Moir|first=Robert D.|last2=Spann|first2=Timothy P.|last3=Lopez-Soler|first3=Reynold I.|last4=Yoon|first4=Miri|last5=Goldman|first5=Anne E.|last6=Khuon|first6=Satya|last7=Goldman|first7=Robert D.|date=2000-04-01|title=Review: The Dynamics of the Nuclear Lamins during the Cell Cycle— Relationship between Structure and Function|url=http://www.sciencedirect.com/science/article/pii/S1047847700942515|journal=Journal of Structural Biology|volume=129|issue=2|pages=324–334|doi=10.1006/jsbi.2000.4251}}</ref>. During this time period, investigations of rat liver nuclei revealed that lamins have an architectural relationship with chromatin and nuclear pores<ref name=":3">{{Cite journal|last=Eriksson|first=John E.|last2=Dechat|first2=Thomas|last3=Grin|first3=Boris|last4=Helfand|first4=Brian|last5=Mendez|first5=Melissa|last6=Pallari|first6=Hanna-Mari|last7=Goldman|first7=Robert D.|date=2009-07-01|title=Introducing intermediate filaments: from discovery to disease|url=http://www.jci.org/articles/view/38339|journal=The Journal of Clinical Investigation|language=en|volume=119|issue=7|doi=10.1172/JCI38339|issn=0021-9738|pmc=2701876|pmid=19587451}}</ref>. Later in 1978, [[immunolabeling]] techniques revealed that lamins are localized at the nuclear envelope under the inner nuclear membrane. It wasn't until 1986 that an analysis of lamin cDNA clones across a variety of species supported that lamins belong to the [[intermediate filament]] (IF) protein family<ref name=":2" />. Further investigations found evidence that supports that all IF proteins arose from a common lamin-like ancestor. This theory is based on the observation that organisms that contain IF necessarily contain lamins as well; however, the presence of lamins is not a requirement for simultaneously containing IF. Furthermore, sequence comparisons between lamins and IF proteins support that an amino-acid sequence that is characteristic of lamins is found in early forms of IF proteins. This sequence is lost in later forms of IF proteins, suggesting that the structure of later intermediate filaments diverged<ref name=":4">{{Cite journal|last=Dittmer|first=Travis A|last2=Misteli|first2=Tom|date=2011-01-01|title=The lamin protein family|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3219962/|journal=Genome Biology|volume=12|issue=5|pages=222|doi=10.1186/gb-2011-12-5-222|issn=1465-6906|pmc=3219962|pmid=21639948}}</ref><ref>{{Cite journal|last=Cooper|first=Geoffrey M.|date=2000-01-01|title=Intermediate Filaments|url=https://www.ncbi.nlm.nih.gov/books/NBK9834/|language=en}}</ref>. Studies of lamins became more popular in the 1990’s when it was discovered that mutations in the genes that code for lamins can be related to muscular dystrophies, cardiomyopathies, and neuropathies<ref name=":5">{{Cite news|url=http://www.hopkinsmedicine.org/institute_basic_biomedical_sciences/news_events/articles_and_stories/aging/200611_a_comeback_for_the_ages.html|title=A Comeback for the Ages: Lamin’s connection with aging has reinvigorated research|last=Simpkins|first=Beth|access-date=2016-11-24}}</ref><ref name=":6">{{Cite journal|last=Young|first=Stephen G.|last2=Jung|first2=Hea-Jin|last3=Lee|first3=John M.|last4=Fong|first4=Loren G.|date=2016-11-24|title=Nuclear Lamins and Neurobiology|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135577/|journal=Molecular and Cellular Biology|volume=34|issue=15|pages=2776–2785|doi=10.1128/MCB.00486-14|issn=0270-7306|pmc=4135577|pmid=24842906}}</ref>. Current research is being performed to develop treatment methods for the aforementioned [[laminopathies]] and to investigate the role lamins play in the aging process.

== Structure ==
The structure of lamins is composed of three units that are common among intermediate filaments: a central α-helical rod domain containing [[Heptad repeat|heptad]] repeats surrounded by globular N and C-terminal domains. The N-terminal is shorter and located at the top (head) while the C-terminal is longer and located at the end (tail)<ref name=":0" /><ref name=":7">{{Cite journal|last=Dechat|first=Thomas|last2=Pfleghaar|first2=Katrin|last3=Sengupta|first3=Kaushik|last4=Shimi|first4=Takeshi|last5=Shumaker|first5=Dale K.|last6=Solimando|first6=Liliana|last7=Goldman|first7=Robert D.|date=2008-04-01|title=Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin|url=http://genesdev.cshlp.org/content/22/7/832|journal=Genes & Development|language=en|volume=22|issue=7|pages=832–853|doi=10.1101/gad.1652708|issn=0890-9369|pmc=2732390|pmid=18381888}}</ref>. Lamins contain a unique structure of the heptad repeats due to its continuity along with an additional six hepatds<ref>{{Cite journal|last=Goldman|first=Robert D.|last2=Gruenbaum|first2=Yosef|last3=Moir|first3=Robert D.|last4=Shumaker|first4=Dale K.|last5=Spann|first5=Timothy P.|date=2002-03-01|title=Nuclear lamins: building blocks of nuclear architecture|url=http://genesdev.cshlp.org/content/16/5/533|journal=Genes & Development|language=en|volume=16|issue=5|pages=533–547|doi=10.1101/gad.960502|issn=0890-9369|pmid=11877373}}</ref>. While the head domain of lamins is fairly consistent, the composition of the tail domain varies based on the type of lamin. However, all C-terminus domains contain a [[nuclear localization sequence]] (NLS). Similar to other IF proteins, lamins self-assemble into more complex structures. The basic unit of these structures is a coiled-coil dimer. The dimers arrange themselves in a head-to-tail manner, allowing for the formation of a protofilament. As these protofilaments aggregate, they form lamin filaments. Lamins of higher level organisms, such as vertebrates, continue to assemble into paracrystalline arrays<ref name=":0" />. These complex structures allow nuclear lamins to perform their specialized functions in maintaining the shape of the nucleus as well as roles during mitosis and apoptosis.


==A- and B-types==
==A- and B-types==
Lamins are divided into two major categories: A- and B-types. These subdivisions are based on similarities in cDNA sequences, structural features, isoelectric points, and expression trends<ref name=":0" /><ref name=":3" />.
In [[animal]] cells, there are A- and B-type lamins, which differ in their length and [[isoelectric point]] (pI). Human cells have three differentially regulated [[gene]]s.

=== A-type Lamins ===
A-type lamins are characterized by a neutral [[isoelectric point]], and they are typically displayed during later stages of embryonic development. Expressed in differentiated cells, A-type lamins originate from the ''LMNA'' gene<ref name=":8">{{Cite journal|last=Stuurman|first=Nico|last2=Heins|first2=Susanne|last3=Aebi|first3=Ueli|date=1998-01-01|title=Nuclear Lamins: Their Structure, Assembly, and Interactions|url=http://www.sciencedirect.com/science/article/pii/S1047847798939879|journal=Journal of Structural Biology|volume=122|issue=1|pages=42–66|doi=10.1006/jsbi.1998.3987}}</ref>. Two isoforms, lamins A and C, can be created from this gene via alternative splicing. This creates a high amount of homology between the isoforms<ref name=":2" />. Unlike lamin C, Lamin A is generated in a precursor form called prelamin A. Prelamin A and lamin C differ in structure only at the carboxyl-terminus. Here, prelamin A contains two extra exons that lamin C lacks. Furthermore, lamin C contains six unique amino-acid residues while prelamin A contains ninety-eight residues not found in the other isoform<ref name=":6" />. A CaaX motif is found within the unique residues in prelamin A. Due to the presence of the CaaX motif, prelamin A undergoes a series of [[Post-translational modification|posttranslational modifications]] to become mature lamin A. These steps include farnesylation of the carboxyl-terminal cysteine, endoproteolytic release of the terminal amino acids, carboxymethalation of the accessable farnesylcysteine, and removal of the final fifteen residues by a zinc metalloprotease. The very first modification involving farnesylation of prelamin A is crucial to the development of mature lamin A. Isoform Lamin C does not undergo posttranslational modifications<ref name=":6" /><ref name=":9">{{Cite journal|last=Dechat|first=Thomas|last2=Adam|first2=Stephen A.|last3=Goldman|first3=Robert D.|date=2009-01-01|title=Nuclear lamins and chromatin: When structure meets function|url=http://www.sciencedirect.com/science/article/pii/S006525710800054X|journal=Advances in Enzyme Regulation|volume=49|issue=1|pages=157–166|doi=10.1016/j.advenzreg.2008.12.003|pmc=3253622|pmid=19154754}}</ref>. Some studies have demonstrated that lamins A and C are not required for the formation of the nuclear lamina, yet disruptions in the ''LMNA'' gene can contribute to physical and mental limitations<ref>{{Cite journal|last=Burke|first=Brian|date=2001-04-30|title=Lamins and Apoptosis|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2190563/|journal=The Journal of Cell Biology|volume=153|issue=3|pages=f5–f7|issn=0021-9525|pmc=2190563|pmid=11331313}}</ref>.


=== B-type Lamins ===
* B-type lamins are present in every cell. B type lamins, B1 and B2, are expressed from the [[LMNB1]] and [[LMNB2]] genes on 5q23 and 19q13, respectively.
B-type lamins are characterized by an acidic isoelectirc point, and they are typically expressed in every cell<ref name=":8" /><ref name=":10">{{Cite journal|last=Gruenbaum|first=Yosef|last2=Wilson|first2=Katherine L.|last3=Harel|first3=Amnon|last4=Goldberg|first4=Michal|last5=Cohen|first5=Merav|date=2000-04-01|title=Review: Nuclear Lamins—Structural Proteins with Fundamental Functions|url=http://www.sciencedirect.com/science/article/pii/S1047847700942163|journal=Journal of Structural Biology|volume=129|issue=2|pages=313–323|doi=10.1006/jsbi.2000.4216}}</ref>. As with A-type lamins, there are multiple isoforms of B-type lamins, the most common being lamins B1 and B2. They are produced from two separate genes, ''LMNB1'' and ''LMNB2'', respectively<ref name=":6" />. Similar to prelamin A, B-type lamins also contain a CaaX motif at the C-terminus. This marker causes the same sequence of [[Post-translational modification|posttranslational modifications]] previously described for prelamin A except for the cleavage step involving a zinc metalloprotease<ref name=":6" /><ref name=":9" />. Further investigations of B-type lamins across multiple species have found evidence that support that B-type lamins existed before A-type lamins. This stems from the similarity in structure of B-type lamins between invertebrates and vertebrates. Furthermore, organisms that only contain a single lamin contain a B-type lamin<ref name=":4" />. Other studies that have investigated the structural similarities and differences between A- and B-type lamins have found that the positions of introns/exons in B-type lamins have been conserved in A-type lamins, with more variations in the A-type lamins. This suggests that the common ancestor of these lamin types was a B-type lamin.
* A-type lamins are expressed only following [[gastrulation]]. Lamin A and C are the most common A-type lamins and are splice variants of the [[LMNA]] gene found at 1q21.


==Function and structure==
==Function==
These proteins localize to two regions of the [[cell nucleus|nuclear compartment]], the [[nuclear lamina]]—a proteinaceous structure layer subjacent to the inner surface of the [[nuclear envelope]] and throughout the nucleoplasm in the nucleoplasmic "veil".


=== Maintenance of Nuclear Shape ===
Comparison of the lamins to cytoskeletal [[intermediate filaments]] shows that lamins have an extra 42 residues (six heptads) within coil 1b. The c-terminal tail domain contains a [[nuclear localization signal]] (NLS), an Ig-fold-like domain, and in most cases a carboxy-terminal CaaX box that is isoprenylated and carboxymethylated (lamin C does not have a CAAX box). Lamin A is further processed to remove the last 15 amino acids and its farnesylated cysteine.
Due to their properties as a type of IF protein, lamins provide support for maintaining the shape of the nucleus. They also play an indirect role in anchoring the nucleus to the ER, forming a continuous unit within the cell. This is accomplished lamin and lamin-interacting proteins (SUN1/SUN2) connecting with proteins on the outer nuclear membrane. These proteins in turn interact with cytoskeletal elements of the [[endoplasmic reticulum]], forming a strong complex that can withstand mechanical stress<ref name=":4" />. Nuclei that lack lamins or have mutated versions are deformed and dysfunctional<ref name=":0" />.


=== Mitosis ===
Lamin A and lamin C form homodimers which associate head to tail.
⚫
During mitosis, lamins are phosphorylated by [[Maturation promoting factor|Mitosis-Promoting Factor]] (MPF), which drives the disassembly of the lamina and the nuclear envelope. This allows chromatin to condense and DNA to be replicated. After chromosome segregation, dephosphorylation of nuclear lamins by a [[phosphatase]] promotes reassembly of the nuclear envelope.


=== Apoptosis ===
⚫
During mitosis, lamins are phosphorylated by [[Maturation promoting factor|Mitosis-Promoting Factor]] (MPF), which drives the disassembly of the lamina and the nuclear envelope. After chromosome segregation, dephosphorylation of nuclear lamins promotes reassembly of the nuclear envelope.
[[Apoptosis]] is a highly organized process of programmed cell death. Lamins are crucial targets for this process due to their close associations with chromatin and the nuclear envelope. Apoptotic enzymes called [[Caspase|caspases]] target lamins and cleave both A- and B-types<ref name=":10" />. This allows chromatin to separate from the nuclear lamina in order to be condensed. As apoptosis continues, cell structures slowly shrink into compartmentalized "blebs." Finally, these apoptotic bodies are digested by [[Phagocyte|phagocytes]]<ref name=":1" />. Studies of apoptosis involving mutant A- and B-type lamins that are resistant to cleavage by caspases show decreased DNA condensation and apoptotic “blebbing” formation, thereby underscoring the important role of lamins in apoptosis<ref name=":7" />.


==Progeria==
==Hutchinson-Gilford Progeria Syndrome==


While lamin mutations can produce a series of disorders ranging from muscular dystrophies to neuropathies, the most common disorder is Hutchinson-Gilford progeria syndrome (HGPS). This genetic condition is characterized by rapid onset aging. Children appear normal at birth, but as they grow and develop they show signs of severe aging. Some of these signs include but are not limited to hair-loss, thinness, joint abnormalities, and retarded motor skills. Affected individuals also develop age-related health problems such as atherosclerosis and high blood pressure. People with this disorder typically die in their early teens, usually by heart attack or stroke<ref name=":1" /><ref>{{Cite web|url=https://ghr.nlm.nih.gov/condition/hutchinson-gilford-progeria-syndrome|title=Hutchinson-Gilford progeria syndrome|last=Reference|first=Genetics Home|website=Genetics Home Reference|access-date=2016-11-24}}</ref>. HGPS is caused by a [[point mutation]] in the ''LMNA'' gene that codes for lamin A. The genetic alteration results in an alternative splice, creating a mutated form of prelamin A that is much shorter and lacks the cleavage site for a zinc metalloprotease. Because prelamin A cannot be properly processed during [[Post-translational modification|posttranslational modifications]], it retains its lipid modification (farnesylation) and remains in the inner nuclear membrane. This disrupts the mechanical stability of the nucleus, resulting in a higher rate of cell death and therefore a higher rate of aging<ref name=":1" />.
Mutations in lamin A (''LMNA'') cause [[Progeria|Hutchinson–Gilford progeria syndrome]], a dramatic form of [[Progeroid syndromes|premature aging]].<ref name="pmid12714972">{{cite journal |vauthors=Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS |title=Recurrent de novo point mutations in lamin A cause Hutchinson–Gilford progeria syndrome |journal=Nature |volume=423 |issue=6937 |pages=293–8 |year=2003 |pmid=12714972 |doi=10.1038/nature01629 |url=}}</ref> Normally, A-type lamins promote genetic stability by maintaining the levels of proteins with key roles in DNA double-strand break repair during the processes of [[non-homologous end joining]] and [[homologous recombination]].<ref name="pmid21701264">{{cite journal |vauthors=Redwood AB, Perkins SM, Vanderwaal RP, Feng Z, Biehl KJ, Gonzalez-Suarez I, Morgado-Palacin L, Shi W, Sage J, Roti-Roti JL, Stewart CL, Zhang J, Gonzalo S |title=A dual role for A-type lamins in DNA double-strand break repair |journal=Cell Cycle |volume=10 |issue=15 |pages=2549–60 |year=2011 |pmid=21701264 |pmc=3180193 |doi=10.4161/cc.10.15.16531 |url=}}</ref> Mouse cells deficient for maturation of prelamin A show increased DNA damage and chromosome aberrations and are more sensitive to DNA damaging agents.<ref name="pmid15980864">{{cite journal |vauthors=Liu B, Wang J, Chan KM, Tjia WM, Deng W, Guan X, Huang JD, Li KM, Chau PY, Chen DJ, Pei D, Pendas AM, Cadiñanos J, López-Otín C, Tse HF, Hutchison C, Chen J, Cao Y, Cheah KS, Tryggvason K, Zhou Z |title=Genomic instability in laminopathy-based premature aging |journal=Nat. Med. |volume=11 |issue=7 |pages=780–5 |year=2005 |pmid=15980864 |doi=10.1038/nm1266 |url=}}</ref> In the Hutchinson–Gilford progeria syndrome, the inability to adequately repair DNA damages may cause aspects of premature aging.


Current studies are investigating the effects of [[Farnesyltransferase inhibitor|farneysyl-transferase inhibitors]] (FTIs) to see if farnesyl attachment can be inhibited during [[Post-translational modification|posttranslational modification]] of prelamin A in order to treat patients with HGPS<ref name=":5" />.
==See also==
==See also==
* [[Intermediate filament]]
* [[Intermediate filament]]

Revision as of 23:45, 24 November 2016

Not to be confused with Laminins.

Nuclear lamins, also known as Class V intermediate filaments, are fibrous proteins providing structural function and transcriptional regulation in the cell nucleus. Nuclear lamins interact with membrane-associated proteins to form the nuclear lamina on the interior of the nuclear envelope. Lamins are present in all members of the kingdom Animalia (Metazoa), but are not found in unicellular organisms, plants, or fungi[1][2]. Lamin proteins are involved in the disassembling and reforming of the nuclear envelope during mitosis, the positioning of nuclear pores, and programmed cell death. Mutations in lamin genes can result in laminopathies, some of which are potentially lethal disorders.

Brief History of Lamins

Nuclear lamins were first identified using electron-microscopy. However, they were not recognized as vital components of nuclear structural support until 1975[3]. During this time period, investigations of rat liver nuclei revealed that lamins have an architectural relationship with chromatin and nuclear pores[4]. Later in 1978, immunolabeling techniques revealed that lamins are localized at the nuclear envelope under the inner nuclear membrane. It wasn't until 1986 that an analysis of lamin cDNA clones across a variety of species supported that lamins belong to the intermediate filament (IF) protein family[3]. Further investigations found evidence that supports that all IF proteins arose from a common lamin-like ancestor. This theory is based on the observation that organisms that contain IF necessarily contain lamins as well; however, the presence of lamins is not a requirement for simultaneously containing IF. Furthermore, sequence comparisons between lamins and IF proteins support that an amino-acid sequence that is characteristic of lamins is found in early forms of IF proteins. This sequence is lost in later forms of IF proteins, suggesting that the structure of later intermediate filaments diverged[5][6]. Studies of lamins became more popular in the 1990’s when it was discovered that mutations in the genes that code for lamins can be related to muscular dystrophies, cardiomyopathies, and neuropathies[7][8]. Current research is being performed to develop treatment methods for the aforementioned laminopathies and to investigate the role lamins play in the aging process.

Structure

The structure of lamins is composed of three units that are common among intermediate filaments: a central α-helical rod domain containing heptad repeats surrounded by globular N and C-terminal domains. The N-terminal is shorter and located at the top (head) while the C-terminal is longer and located at the end (tail)[1][9]. Lamins contain a unique structure of the heptad repeats due to its continuity along with an additional six hepatds[10]. While the head domain of lamins is fairly consistent, the composition of the tail domain varies based on the type of lamin. However, all C-terminus domains contain a nuclear localization sequence (NLS). Similar to other IF proteins, lamins self-assemble into more complex structures. The basic unit of these structures is a coiled-coil dimer. The dimers arrange themselves in a head-to-tail manner, allowing for the formation of a protofilament. As these protofilaments aggregate, they form lamin filaments. Lamins of higher level organisms, such as vertebrates, continue to assemble into paracrystalline arrays[1]. These complex structures allow nuclear lamins to perform their specialized functions in maintaining the shape of the nucleus as well as roles during mitosis and apoptosis.

A- and B-types

Lamins are divided into two major categories: A- and B-types. These subdivisions are based on similarities in cDNA sequences, structural features, isoelectric points, and expression trends[1][4].

A-type Lamins

A-type lamins are characterized by a neutral isoelectric point, and they are typically displayed during later stages of embryonic development. Expressed in differentiated cells, A-type lamins originate from the LMNA gene[11]. Two isoforms, lamins A and C, can be created from this gene via alternative splicing. This creates a high amount of homology between the isoforms[3]. Unlike lamin C, Lamin A is generated in a precursor form called prelamin A. Prelamin A and lamin C differ in structure only at the carboxyl-terminus. Here, prelamin A contains two extra exons that lamin C lacks. Furthermore, lamin C contains six unique amino-acid residues while prelamin A contains ninety-eight residues not found in the other isoform[8]. A CaaX motif is found within the unique residues in prelamin A. Due to the presence of the CaaX motif, prelamin A undergoes a series of posttranslational modifications to become mature lamin A. These steps include farnesylation of the carboxyl-terminal cysteine, endoproteolytic release of the terminal amino acids, carboxymethalation of the accessable farnesylcysteine, and removal of the final fifteen residues by a zinc metalloprotease. The very first modification involving farnesylation of prelamin A is crucial to the development of mature lamin A. Isoform Lamin C does not undergo posttranslational modifications[8][12]. Some studies have demonstrated that lamins A and C are not required for the formation of the nuclear lamina, yet disruptions in the LMNA gene can contribute to physical and mental limitations[13].

B-type Lamins

B-type lamins are characterized by an acidic isoelectirc point, and they are typically expressed in every cell[11][14]. As with A-type lamins, there are multiple isoforms of B-type lamins, the most common being lamins B1 and B2. They are produced from two separate genes, LMNB1 and LMNB2, respectively[8]. Similar to prelamin A, B-type lamins also contain a CaaX motif at the C-terminus. This marker causes the same sequence of posttranslational modifications previously described for prelamin A except for the cleavage step involving a zinc metalloprotease[8][12]. Further investigations of B-type lamins across multiple species have found evidence that support that B-type lamins existed before A-type lamins. This stems from the similarity in structure of B-type lamins between invertebrates and vertebrates. Furthermore, organisms that only contain a single lamin contain a B-type lamin[5]. Other studies that have investigated the structural similarities and differences between A- and B-type lamins have found that the positions of introns/exons in B-type lamins have been conserved in A-type lamins, with more variations in the A-type lamins. This suggests that the common ancestor of these lamin types was a B-type lamin.

Function

Maintenance of Nuclear Shape

Due to their properties as a type of IF protein, lamins provide support for maintaining the shape of the nucleus. They also play an indirect role in anchoring the nucleus to the ER, forming a continuous unit within the cell. This is accomplished lamin and lamin-interacting proteins (SUN1/SUN2) connecting with proteins on the outer nuclear membrane. These proteins in turn interact with cytoskeletal elements of the endoplasmic reticulum, forming a strong complex that can withstand mechanical stress[5]. Nuclei that lack lamins or have mutated versions are deformed and dysfunctional[1].

Mitosis

During mitosis, lamins are phosphorylated by Mitosis-Promoting Factor (MPF), which drives the disassembly of the lamina and the nuclear envelope. This allows chromatin to condense and DNA to be replicated. After chromosome segregation, dephosphorylation of nuclear lamins by a phosphatase promotes reassembly of the nuclear envelope.

Apoptosis

Apoptosis is a highly organized process of programmed cell death. Lamins are crucial targets for this process due to their close associations with chromatin and the nuclear envelope. Apoptotic enzymes called caspases target lamins and cleave both A- and B-types[14]. This allows chromatin to separate from the nuclear lamina in order to be condensed. As apoptosis continues, cell structures slowly shrink into compartmentalized "blebs." Finally, these apoptotic bodies are digested by phagocytes[2]. Studies of apoptosis involving mutant A- and B-type lamins that are resistant to cleavage by caspases show decreased DNA condensation and apoptotic “blebbing” formation, thereby underscoring the important role of lamins in apoptosis[9].

Hutchinson-Gilford Progeria Syndrome

While lamin mutations can produce a series of disorders ranging from muscular dystrophies to neuropathies, the most common disorder is Hutchinson-Gilford progeria syndrome (HGPS). This genetic condition is characterized by rapid onset aging. Children appear normal at birth, but as they grow and develop they show signs of severe aging. Some of these signs include but are not limited to hair-loss, thinness, joint abnormalities, and retarded motor skills. Affected individuals also develop age-related health problems such as atherosclerosis and high blood pressure. People with this disorder typically die in their early teens, usually by heart attack or stroke[2][15]. HGPS is caused by a point mutation in the LMNA gene that codes for lamin A. The genetic alteration results in an alternative splice, creating a mutated form of prelamin A that is much shorter and lacks the cleavage site for a zinc metalloprotease. Because prelamin A cannot be properly processed during posttranslational modifications, it retains its lipid modification (farnesylation) and remains in the inner nuclear membrane. This disrupts the mechanical stability of the nucleus, resulting in a higher rate of cell death and therefore a higher rate of aging[2].

Current studies are investigating the effects of farneysyl-transferase inhibitors (FTIs) to see if farnesyl attachment can be inhibited during posttranslational modification of prelamin A in order to treat patients with HGPS[7].

See also

References

  1. ^ a b c d e Dechat, Thomas; Adam, Stephen A.; Taimen, Pekka; Shimi, Takeshi; Goldman, Robert D. (2016-11-24). "Nuclear Lamins". Cold Spring Harbor Perspectives in Biology. 2 (11). doi:10.1101/cshperspect.a000547. ISSN 1943-0264. PMC 2964183. PMID 20826548.
  2. ^ a b c d Hardin Jeff, and Bertoni Gregory (2016). Becker's World of the Cell, 9th Edition. Boston, MA: Pearson. ISBN 9780321934925.
  3. ^ a b c Moir, Robert D.; Spann, Timothy P.; Lopez-Soler, Reynold I.; Yoon, Miri; Goldman, Anne E.; Khuon, Satya; Goldman, Robert D. (2000-04-01). "Review: The Dynamics of the Nuclear Lamins during the Cell Cycle— Relationship between Structure and Function". Journal of Structural Biology. 129 (2): 324–334. doi:10.1006/jsbi.2000.4251.
  4. ^ a b Eriksson, John E.; Dechat, Thomas; Grin, Boris; Helfand, Brian; Mendez, Melissa; Pallari, Hanna-Mari; Goldman, Robert D. (2009-07-01). "Introducing intermediate filaments: from discovery to disease". The Journal of Clinical Investigation. 119 (7). doi:10.1172/JCI38339. ISSN 0021-9738. PMC 2701876. PMID 19587451.
  5. ^ a b c Dittmer, Travis A; Misteli, Tom (2011-01-01). "The lamin protein family". Genome Biology. 12 (5): 222. doi:10.1186/gb-2011-12-5-222. ISSN 1465-6906. PMC 3219962. PMID 21639948.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  6. ^ Cooper, Geoffrey M. (2000-01-01). "Intermediate Filaments". {{cite journal}}: Cite journal requires |journal= (help)
  7. ^ a b Simpkins, Beth. "A Comeback for the Ages: Lamin's connection with aging has reinvigorated research". Retrieved 2016-11-24.
  8. ^ a b c d e Young, Stephen G.; Jung, Hea-Jin; Lee, John M.; Fong, Loren G. (2016-11-24). "Nuclear Lamins and Neurobiology". Molecular and Cellular Biology. 34 (15): 2776–2785. doi:10.1128/MCB.00486-14. ISSN 0270-7306. PMC 4135577. PMID 24842906.
  9. ^ a b Dechat, Thomas; Pfleghaar, Katrin; Sengupta, Kaushik; Shimi, Takeshi; Shumaker, Dale K.; Solimando, Liliana; Goldman, Robert D. (2008-04-01). "Nuclear lamins: major factors in the structural organization and function of the nucleus and chromatin". Genes & Development. 22 (7): 832–853. doi:10.1101/gad.1652708. ISSN 0890-9369. PMC 2732390. PMID 18381888.
  10. ^ Goldman, Robert D.; Gruenbaum, Yosef; Moir, Robert D.; Shumaker, Dale K.; Spann, Timothy P. (2002-03-01). "Nuclear lamins: building blocks of nuclear architecture". Genes & Development. 16 (5): 533–547. doi:10.1101/gad.960502. ISSN 0890-9369. PMID 11877373.
  11. ^ a b Stuurman, Nico; Heins, Susanne; Aebi, Ueli (1998-01-01). "Nuclear Lamins: Their Structure, Assembly, and Interactions". Journal of Structural Biology. 122 (1): 42–66. doi:10.1006/jsbi.1998.3987.
  12. ^ a b Dechat, Thomas; Adam, Stephen A.; Goldman, Robert D. (2009-01-01). "Nuclear lamins and chromatin: When structure meets function". Advances in Enzyme Regulation. 49 (1): 157–166. doi:10.1016/j.advenzreg.2008.12.003. PMC 3253622. PMID 19154754.
  13. ^ Burke, Brian (2001-04-30). "Lamins and Apoptosis". The Journal of Cell Biology. 153 (3): f5–f7. ISSN 0021-9525. PMC 2190563. PMID 11331313.
  14. ^ a b Gruenbaum, Yosef; Wilson, Katherine L.; Harel, Amnon; Goldberg, Michal; Cohen, Merav (2000-04-01). "Review: Nuclear Lamins—Structural Proteins with Fundamental Functions". Journal of Structural Biology. 129 (2): 313–323. doi:10.1006/jsbi.2000.4216.
  15. ^ Reference, Genetics Home. "Hutchinson-Gilford progeria syndrome". Genetics Home Reference. Retrieved 2016-11-24.

External links

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