Biology:LMNA

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Short description: Filament protein in the nuclear matrix and nuclear lamina that is required for DNA replication and nuclear organization.


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

LMNA, also known as Lamin A/C is a protein that in humans is encoded by the LMNA gene.[1][2][3] Lamin A/C belongs to the lamin family of proteins.

Function

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

[4]

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.[5] 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.[6]

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

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.[7]

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.[8][9] To date over 1,400 SNPs are known [1]. They can manifest in changes on mRNA, splicing or protein (e.g. Arg471Cys,[10] Arg482Gln,[11] Arg527Leu,[12] Arg527Cys,[13] Ala529Val [14] ) level.

DNA damage

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.[15][16] 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.[17] In progeria, the inadequacy of DNA repair, due to defective LMNA, may cause features of premature aging (see DNA damage theory of aging).

Interactions

LMNA has been shown to interact with:

References

  1. ↑ "Structural organization of the human gene encoding nuclear lamin A and nuclear lamin C". J Biol Chem 268 (22): 16321–16326. 1993. doi:10.1016/S0021-9258(19)85424-8. PMID 8344919. 
  2. ↑ "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. March 1993. doi:10.1007/BF01233534. PMID 8511676. 
  3. ↑ "Chromosomal assignment of human nuclear envelope protein genes LMNA, LMNB1, and LBR by fluorescence in situ hybridization". Genomics 32 (3): 474–8. March 1996. doi:10.1006/geno.1996.0146. PMID 8838815. 
  4. ↑ Buxboim, A.; Swift, J.; Irianto, J.; Spinler, K. R.; Dingal, P. C.; Athirasala, A.; Kao, Y. R.; Cho, S. et al. (2014). "Matrix elasticity regulates lamin-A,C phosphorylation and turnover with feedback to actomyosin". Current Biology 24 (16): 1909–17. doi:10.1016/j.cub.2014.07.001. PMID 25127216. 
  5. ↑ "Molecular ageing in progeroid syndromes: Hutchinson–Gilford progeria syndrome as a model". Immun Ageing 6: 4. 2009. doi:10.1186/1742-4933-6-4. PMID 19379495. 
  6. ↑ "Entrez Gene: LMNA lamin A/C". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4000. 
  7. ↑ "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. 2012. doi:10.1038/ejhg.2012.77. PMID 22549407. 
  8. ↑ "Human laminopathies: nuclei gone genetically awry". Nat. Rev. Genet. 7 (12): 940–52. December 2006. doi:10.1038/nrg1906. PMID 17139325. 
  9. ↑ "The laminopathies: a clinical review". Clin. Genet. 70 (4): 261–74. October 2006. doi:10.1111/j.1399-0004.2006.00677.x. PMID 16965317. https://semanticscholar.org/paper/07014139be8a90c839d3dbbcb6628a6781c41250. 
  10. ↑ "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. 2008. doi:10.1002/ajmg.a.32259. PMID 18348272. 
  11. ↑ "Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy". Hum. Mol. Genet. 9 (1): 109–12. 2002. doi:10.1093/hmg/9.1.109. PMID 10587585. 
  12. ↑ "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. 2012. doi:10.1038/ejhg.2012.77. PMID 22549407. 
  13. ↑ "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. 2008. doi:10.1210/jc.2008-0123. PMID 18796515. 
  14. ↑ "A novel homozygous Ala529Val LMNA mutation in Turkish patients with mandibuloacral dysplasia". J. Clin. Endocrinol. Metab. 90 (9): 5259–64. 2005. doi:10.1210/jc.2004-2560. PMID 15998779. 
  15. ↑ "A dual role for A-type lamins in DNA double-strand break repair". Cell Cycle 10 (15): 2549–60. 2011. doi:10.4161/cc.10.15.16531. PMID 21701264. 
  16. ↑ "DNA repair defects and genome instability in Hutchinson-Gilford Progeria Syndrome". Curr. Opin. Cell Biol. 34: 75–83. 2015. doi:10.1016/j.ceb.2015.05.007. PMID 26079711. 
  17. ↑ "Genomic instability in laminopathy-based premature aging". Nat. Med. 11 (7): 780–5. 2005. doi:10.1038/nm1266. PMID 15980864. 
  18. ↑ "Identification of 12-lipoxygenase interaction with cellular proteins by yeast two-hybrid screening". Biochemistry 39 (12): 3185–91. March 2000. doi:10.1021/bi992664v. PMID 10727209. 
  19. ↑ "Emerin interacts in vitro with the splicing-associated factor, YT521-B". Eur. J. Biochem. 270 (11): 2459–66. June 2003. doi:10.1046/j.1432-1033.2003.03617.x. PMID 12755701. 
  20. ↑ "Association of emerin with nuclear and cytoplasmic actin is regulated in differentiating myoblasts". Biochem. Biophys. Res. Commun. 303 (3): 764–70. April 2003. doi:10.1016/S0006-291X(03)00415-7. PMID 12670476. 
  21. ↑ "Interaction between emerin and nuclear lamins". J. Biochem. 129 (2): 321–7. February 2001. doi:10.1093/oxfordjournals.jbchem.a002860. PMID 11173535. 
  22. ↑ "Direct interaction between emerin and lamin A". Biochem. Biophys. Res. Commun. 267 (3): 709–14. January 2000. doi:10.1006/bbrc.1999.2023. PMID 10673356. 
  23. ↑ "Prenylated prelamin A interacts with Narf, a novel nuclear protein". J. Biol. Chem. 274 (42): 30008–18. October 1999. doi:10.1074/jbc.274.42.30008. PMID 10514485. 
  24. ↑ "A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies". Hum. Mol. Genet. 11 (7): 769–77. April 2002. doi:10.1093/hmg/11.7.769. PMID 11929849. 
  25. ↑ "Lamin A/C binding protein LAP2alpha is required for nuclear anchorage of retinoblastoma protein". Mol. Biol. Cell 13 (12): 4401–13. December 2002. doi:10.1091/mbc.E02-07-0450. PMID 12475961. 
  26. ↑ "Lamina-associated polypeptide 2alpha binds intranuclear A-type lamins". J. Cell Sci. 113 (19): 3473–84. October 2000. doi:10.1242/jcs.113.19.3473. PMID 10984438. 
  27. ↑ "In vivo and in vitro interaction between human transcription factor MOK2 and nuclear lamin A/C". Nucleic Acids Res. 30 (21): 4634–42. November 2002. doi:10.1093/nar/gkf587. PMID 12409453. 
  28. ↑ "Resveratrol Rescues SIRT1-Dependent Adult Stem Cell Decline and Alleviates Progeroid Features in Laminopathy-Based Progeria". Cell Metabolism 16 (6): 738–750. 2012. doi:10.1016/j.cmet.2012.11.007. PMID 23217256. 

Further reading

External links




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