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Prelamin-A/C

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(Redirected from Lamin A)

LMNA
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesLMNA, CDCD1, CDDC, CMD1A, CMT2B1, EMD2, FPL, FPLD, FPLD2, HGPS, IDC, LDP1, LFP, LGMD1B, LMN1, LMNC, LMNL1, PRO1, lamin A/C, MADA, A-type lamin
External IDsOMIM: 150330; MGI: 96794; HomoloGene: 41321; GeneCards: LMNA; OMA:LMNA - orthologs
Orthologs
SpeciesHumanMouse
Entrez

4000

16905

Ensembl

ENSG00000160789

ENSMUSG00000028063

UniProt

P02545

P48678

RefSeq (mRNA)

NM_001002011
NM_001111102
NM_019390

RefSeq (protein)

NP_001002011
NP_001104572
NP_062263

Location (UCSC)Chr 1: 156.08 – 156.14 MbChr 3: 88.39 – 88.42 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Prelamin-A/C, or lamin A/C is a protein that in humans is encoded by the LMNA gene.[5][6][7] Lamin A/C belongs to the lamin family of proteins.

Function

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Biogenesis of lamin A in normal cells and the failure to generate mature lamin A in Hutchinson–Gilford progeria syndrome.

[8]

In the setting of ZMPSTE24 deficiency, the final step of lamin processing does not occur, resulting in an accumulation of farnesyl-prelamin A. In Hutchinson–Gilford progeria syndrome, a 50-amino acid deletion in prelamin A (amino acids 607–656) removes the site for the second endoproteolytic cleavage. Consequently, no mature lamin A is formed, and a farnesylated mutant prelamin A (progerin) accumulates in cells.[9] The nuclear lamina consist of a two-dimensional matrix of proteins located next to the inner nuclear membrane. The lamin family of proteins make up the matrix and are highly conserved in evolution. During mitosis, the lamina matrix is reversibly disassembled as the lamin proteins are phosphorylated. Lamin proteins are thought to be involved in nuclear stability, chromatin structure and gene expression. Vertebrate lamins consist of two types, A and B. Through alternate splicing, this gene encodes three type A lamin isoforms.[10]

Early in mitosis, maturation promoting factor (abbreviated MPF, also called mitosis-promoting factor or M-phase-promoting factor) phosphorylates specific serine residues in all three nuclear lamins, causing depolymerization of the lamin intermediate filaments. The phosphorylated lamin B dimers remain associated with the nuclear membrane via their isoprenyl anchor. Lamin A is targeted to the nuclear membrane by an isoprenyl group but it is cleaved shortly after arriving at the membrane. It stays associated with the membrane through protein-protein interactions of itself and other membrane associated proteins, such as TOR1AIP1 (LAP1). Depolymerization of the nuclear lamins leads to disintegration of the nuclear envelope. Transfection experiments demonstrate that phosphorylation of human lamin A is required for lamin depolymerization, and thus for disassembly of the nuclear envelope, which normally occurs early in mitosis.

Clinical significance

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Wild type (left) and mutated (right) form of the Ig-fold of lamin A (LMNA, PDB: 1IFR). Normally, arginine 527 (blue) forms a salt bridge with glutamate 537 (magenta), but R527L substitution results in breaking this interaction (leucine is too short to reach glutamate). Models are presented in surface (upper) and in cartoon (lower) representation.[11]

Mutations in the LMNA gene are associated with several diseases, including Emery–Dreifuss muscular dystrophy, familial partial lipodystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy, Charcot–Marie–Tooth disease, and restrictive dermopathy. A truncated version of lamin A, commonly known as progerin, causes Hutchinson-Gilford-Progeria syndrome.[12][13] To date over 1,400 SNPs are known [1]. They can manifest in changes on mRNA, splicing or protein (e.g. Arg471Cys,[14] Arg482Gln,[15] Arg527Leu,[16] Arg527Cys,[17] Ala529Val [18] ) level.

DNA damage

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DNA double-strand damages can be repaired by either homologous recombination (HR) or non-homologous end joining (NHEJ). LMNA promotes genetic stability by maintaining the levels of proteins that have key roles in HR and NHEJ.[19][20] Mouse cells that are deficient for maturation of prelamin A have increased DNA damage and chromosome aberrations, and show increased sensitivity to DNA damaging agents.[21] In progeria, the inadequacy of DNA repair, due to defective LMNA, may cause features of premature aging (see DNA damage theory of aging).

Interactions

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LMNA has been shown to interact with:

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000160789 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000028063 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Lin F, Worman HJ (1993). "Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C". J Biol Chem. 268 (22): 16321–16326. doi:10.1016/S0021-9258(19)85424-8. PMID 8344919.
  6. ^ Kamat AK, Rocchi M, Smith DI, Miller OJ (March 1993). "Lamin A/C gene and a related sequence map to human chromosomes 1q12.1-q23 and 10". Somat. Cell Mol. Genet. 19 (2): 203–8. doi:10.1007/BF01233534. PMID 8511676. S2CID 32913788.
  7. ^ Wydner KL, McNeil JA, Lin F, Worman HJ, Lawrence JB (March 1996). "Chromosomal assignment of human nuclear envelope protein genes LMNA, LMNB1, and LBR by fluorescence in situ hybridization". Genomics. 32 (3): 474–8. doi:10.1006/geno.1996.0146. PMID 8838815.
  8. ^ Buxboim A, Swift J, Irianto J, Spinler KR, Dingal PC, Athirasala A, Kao YR, Cho S, Harada T, Shin JW, Discher DE (2014). "Matrix elasticity regulates lamin-A,C phosphorylation and turnover with feedback to actomyosin". Current Biology. 24 (16): 1909–17. Bibcode:2014CBio...24.1909B. doi:10.1016/j.cub.2014.07.001. PMC 4373646. PMID 25127216.
  9. ^ Coutinho HD, Falcão-Silva VS, Gonçalves GF, da Nóbrega RB (2009). "Molecular ageing in progeroid syndromes: Hutchinson–Gilford progeria syndrome as a model". Immun Ageing. 6: 4. doi:10.1186/1742-4933-6-4. PMC 2674425. PMID 19379495.
  10. ^ "Entrez Gene: LMNA lamin A/C".
  11. ^ Al-Haggar M, Madej-Pilarczyk A, Kozlowski L, Bujnicki JM, Yahia S, Abdel-Hadi D, Shams A, Ahmad N, Hamed S, Puzianowska-Kuznicka M (2012). "A novel homozygous p.Arg527Leu LMNA mutation in two unrelated Egyptian families causes overlapping mandibuloacral dysplasia and progeria syndrome". Eur J Hum Genet. 20 (11): 1134–40. doi:10.1038/ejhg.2012.77. PMC 3476705. PMID 22549407.
  12. ^ Capell BC, Collins FS (December 2006). "Human laminopathies: nuclei gone genetically awry". Nat. Rev. Genet. 7 (12): 940–52. doi:10.1038/nrg1906. PMID 17139325. S2CID 13438737.
  13. ^ Rankin J, Ellard S (October 2006). "The laminopathies: a clinical review". Clin. Genet. 70 (4): 261–74. doi:10.1111/j.1399-0004.2006.00677.x. PMID 16965317. S2CID 7234475.
  14. ^ Zirn B, Kress W, Grimm T, Berthold LD, Neubauer B, Kuchelmeister K, Müller U, Hahn A (2008). "Association of homozygous LMNA mutation R471C with new phenotype: mandibuloacral dysplasia, progeria, and rigid spine muscular dystrophy". Am J Med Genet A. 146A (8): 1049–1054. doi:10.1002/ajmg.a.32259. PMID 18348272. S2CID 205309256.
  15. ^ Cao H, Hegele RA (2002). "Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy". Hum. Mol. Genet. 9 (1): 109–12. doi:10.1093/hmg/9.1.109. PMID 10587585.
  16. ^ Al-Haggar M, Madej-Pilarczyk A, Kozlowski L, Bujnicki JM, Yahia S, Abdel-Hadi D, Shams A, Ahmad N, Hamed S, Puzianowska-Kuznicka M (2012). "A novel homozygous p.Arg527Leu LMNA mutation in two unrelated Egyptian families causes overlapping mandibuloacral dysplasia and progeria syndrome". Eur J Hum Genet. 20 (11): 1134–40. doi:10.1038/ejhg.2012.77. PMC 3476705. PMID 22549407.
  17. ^ Agarwal AK, Kazachkova I, Ten S, Garg A (2008). "Severe mandibuloacral dysplasia-associated lipodystrophy and progeria in a young girl with a novel homozygous Arg527Cys LMNA mutation". J Clin Endocrinol Metab. 93 (12): 4617–4623. doi:10.1210/jc.2008-0123. PMC 2626450. PMID 18796515.
  18. ^ Garg A, Cogulu O, Ozkinay F, Onay H, Agarwal AK (2005). "A novel homozygous Ala529Val LMNA mutation in Turkish patients with mandibuloacral dysplasia". J. Clin. Endocrinol. Metab. 90 (9): 5259–64. doi:10.1210/jc.2004-2560. PMID 15998779.
  19. ^ 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 (2011). "A dual role for A-type lamins in DNA double-strand break repair". Cell Cycle. 10 (15): 2549–60. doi:10.4161/cc.10.15.16531. PMC 3180193. PMID 21701264.
  20. ^ Gonzalo S, Kreienkamp R (2015). "DNA repair defects and genome instability in Hutchinson-Gilford Progeria Syndrome". Curr. Opin. Cell Biol. 34: 75–83. doi:10.1016/j.ceb.2015.05.007. PMC 4522337. PMID 26079711.
  21. ^ 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 (2005). "Genomic instability in laminopathy-based premature aging". Nat. Med. 11 (7): 780–5. doi:10.1038/nm1266. PMID 15980864. S2CID 11798376.
  22. ^ Tang K, Finley RL, Nie D, Honn KV (March 2000). "Identification of 12-lipoxygenase interaction with cellular proteins by yeast two-hybrid screening". Biochemistry. 39 (12): 3185–91. doi:10.1021/bi992664v. PMID 10727209.
  23. ^ Wilkinson FL, Holaska JM, Zhang Z, Sharma A, Manilal S, Holt I, Stamm S, Wilson KL, Morris GE (June 2003). "Emerin interacts in vitro with the splicing-associated factor, YT521-B". Eur. J. Biochem. 270 (11): 2459–66. doi:10.1046/j.1432-1033.2003.03617.x. PMID 12755701. S2CID 5963743.
  24. ^ Lattanzi G, Cenni V, Marmiroli S, Capanni C, Mattioli E, Merlini L, Squarzoni S, Maraldi NM (April 2003). "Association of emerin with nuclear and cytoplasmic actin is regulated in differentiating myoblasts". Biochem. Biophys. Res. Commun. 303 (3): 764–70. doi:10.1016/S0006-291X(03)00415-7. PMID 12670476.
  25. ^ Sakaki M, Koike H, Takahashi N, Sasagawa N, Tomioka S, Arahata K, Ishiura S (February 2001). "Interaction between emerin and nuclear lamins". J. Biochem. 129 (2): 321–7. doi:10.1093/oxfordjournals.jbchem.a002860. PMID 11173535.
  26. ^ Clements L, Manilal S, Love DR, Morris GE (January 2000). "Direct interaction between emerin and lamin A". Biochem. Biophys. Res. Commun. 267 (3): 709–14. doi:10.1006/bbrc.1999.2023. PMID 10673356.
  27. ^ Barton RM, Worman HJ (October 1999). "Prenylated prelamin A interacts with Narf, a novel nuclear protein". J. Biol. Chem. 274 (42): 30008–18. doi:10.1074/jbc.274.42.30008. PMID 10514485.
  28. ^ Lloyd DJ, Trembath RC, Shackleton S (April 2002). "A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies". Hum. Mol. Genet. 11 (7): 769–77. doi:10.1093/hmg/11.7.769. PMID 11929849.
  29. ^ Markiewicz E, Dechat T, Foisner R, Quinlan RA, Hutchison CJ (December 2002). "Lamin A/C binding protein LAP2alpha is required for nuclear anchorage of retinoblastoma protein". Mol. Biol. Cell. 13 (12): 4401–13. doi:10.1091/mbc.E02-07-0450. PMC 138642. PMID 12475961.
  30. ^ Dechat T, Korbei B, Vaughan OA, Vlcek S, Hutchison CJ, Foisner R (October 2000). "Lamina-associated polypeptide 2alpha binds intranuclear A-type lamins". J. Cell Sci. 113 (19): 3473–84. doi:10.1242/jcs.113.19.3473. PMID 10984438.
  31. ^ Dreuillet C, Tillit J, Kress M, Ernoult-Lange M (November 2002). "In vivo and in vitro interaction between human transcription factor MOK2 and nuclear lamin A/C". Nucleic Acids Res. 30 (21): 4634–42. doi:10.1093/nar/gkf587. PMC 135794. PMID 12409453.
  32. ^ Liu B, Ghosh S, Yang X, Zheng H, Liu X, Wang Z, Jin G, Zheng B, Kennedy BK, Suh Y, Kaeberlein M, Tryggvason K, Zhou Z (2012). "Resveratrol Rescues SIRT1-Dependent Adult Stem Cell Decline and Alleviates Progeroid Features in Laminopathy-Based Progeria". Cell Metabolism. 16 (6): 738–750. doi:10.1016/j.cmet.2012.11.007. PMID 23217256.

Further reading

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