LMNA

(Preusmjereno sa Lamin A/C)

LMNA, poznat i kao lamin A/C je protein koji je kod ljudi kodiran genom LMNA.[5][6][7] Lamin A/C pripada porodici laminskih proteina.

LMNA
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

1IFR, 1IVT, 1X8Y, 2XV5, 2YPT, 3GEF, 3V4Q, 3V4W, 3V5B

Identifikatori
AliasiLMNA
Vanjski ID-jeviOMIM: 150330 MGI: 96794 HomoloGene: 41321 GeneCards: LMNA
Lokacija gena (čovjek)
Hromosom 1 (čovjek)
Hrom.Hromosom 1 (čovjek)[1]
Hromosom 1 (čovjek)
Genomska lokacija za LMNA
Genomska lokacija za LMNA
Bend1q22Početak156,082,573 bp[1]
Kraj156,140,081 bp[1]
Lokacija gena (miš)
Hromosom 3 (miš)
Hrom.Hromosom 3 (miš)[2]
Hromosom 3 (miš)
Genomska lokacija za LMNA
Genomska lokacija za LMNA
Bend3 F1|3 38.84 cMPočetak88,387,454 bp[2]
Kraj88,417,263 bp[2]
Obrazac RNK ekspresije




Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija structural molecule activity
GO:0001948, GO:0016582 vezivanje za proteine
vezivanje identičnih proteina
Ćelijska komponenta Jedarna lamina
citosol
nuclear speck
lamin filament
perinuklearno područje citoplazme
Intermedijarni filament
jedro
GO:0005578 Vanćelijski matriks
Jedarna membrana
nukleoplazma
nuclear envelope
Biološki proces regulation of cell migration
nucleus organization
establishment or maintenance of microtubule cytoskeleton polarity
negative regulation of release of cytochrome c from mitochondria
negative regulation of extrinsic apoptotic signaling pathway
muscle organ development
regulation of protein localization to nucleus
IRE1-mediated unfolded protein response
mitotic nuclear membrane disassembly
protein localization to nucleus
mitotic nuclear membrane reassembly
ventricular cardiac muscle cell development
cellular response to hypoxia
GO:1901313 positive regulation of gene expression
negative regulation of mesenchymal cell proliferation
nuclear envelope organization
negative regulation of cell population proliferation
regulation of telomere maintenance
negative regulation of cardiac muscle hypertrophy in response to stress
protein import into nucleus
regulation of protein stability
positive regulation of histone H3-K9 trimethylation
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez
Ensembl
UniProt
RefSeq (mRNK)
NM_001257374
NM_001282624
NM_001282625
NM_001282626
NM_005572

NM_170707
NM_170708

NM_001002011
NM_001111102
NM_019390

RefSeq (bjelančevina)
NP_001244303
NP_001269553
NP_001269554
NP_001269555
NP_005563

NP_733821
NP_733822

NP_001002011
NP_001104572
NP_062263

Lokacija (UCSC)Chr 1: 156.08 – 156.14 MbChr 3: 88.39 – 88.42 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

Funkcija

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Biogeneza lamina A u normalnim ćelijama i neuspjeh u stvaranju zrelog lamina A u progeriji Hutchinson-Gilfordovog sindroma[8]

U postavci nedostatka ZMPSTE24, ne dolazi do završnog koraka obrade lamina, što rezultira akumulacijom farnezil-prelamina A. U Hutchinson-Gilfordovom progerijskom sindromu, delecija 50 aminokiselina u prelaminu A (aminokiseline 607–656) uklanja mjesto za drugo endoproteolsko cijepanje. Slijedom toga, ne stvara se zreli lamin A, a u ćelijama se nakuplja farnezilirani mutant prelamin A (progerin).[9] Jedarna lamina sastoji se od dvodimenzijske matrice proteina, koja se nalazi pored unutrašnje jedarne membrane. Porodica laminskih proteina čine matriks i u evoluciji visoko su konzervirani. Tokom mitoze, matrica lamina se reverzibilno rastavlja jer su lamin proteini fosforilirani. Smatra se da su proteini lamina uključeni u jedarnu stabilnost, hromatinsku strukturu i ekspresiju gena[]. Lamini kičmenjaka sastoje se od dva tipa, A i B. Kroz alternativno spajanje, ovaj gen kodira tri izoforme lamina tipa A.[10]

U ranoj fazi mitoze, faktor podsticanja sazrijevanja (skraćeno MPF, također nazvan faktor koji promovira mitozu ili faktor koji promovira M-fazu) fosforilira specifične ostatke serina u sva tri jedarna lamina, uzrokujući depolimerizaciju srednjih laminskih vlakana. Fosforilirani dimeri lamina B ostaju povezani sa jedarnom membranom, preko njihovog izoprenilskog sidra. Lamin A je na jedrovu membranu usmjeren izoprenilnom grupom, ali se cijepa nedugo nakon dolaska na membranu. Ostaje sa njom povezan tokom interakcije između proteina i proteina, kao i drugih proteina povezanih s membranom, kao što je LAP1. Depolimerizacija nuklearnih lamina dovodi do raspada jedarne ovojnice. Tranfekcijski eksperimenti pokazuju da je fosforilacija ljudskog lamina A potrebna za depolimerizaciju lamina, a time i za rastavljanje jedarne ovojnice, koja se obično javlja rano u mitozi.

Klinički značaj

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Divlji tip (lijevo) i mutirani (desni) oblik Ig-nabora lamina A (LMNA, PDB: 1IFR).
Uobičajeno, arginin 527 (plavi) formira most soli sa glutamatom 537 (magenta), ali supstitucija R527L rezultira prekidom ove interakcije (leucin je prekratak da bi mogao doći do glutamata).
Modeli su predstavljeni u površinskom (gornjem) i crtanom (donjem) prikazu.[11]

Mutacije u genu LMNA povezane su s nekoliko bolesti, uključujući Emery-Dreifussovu mišićnu distrofiju, porodičnu parcijalnu lipodistrofiju, mišićnu distrofiju udovi-pojas, proširenu kardiomiopatiju Charcot-Marie-Toothovu bolest i restriktivnu dermopatiju. Skraćena verzija lamina A, poznata kao progerin, uzrokuje Hutchinson-Gilford progerijski sindrom.[12][13] Do danas poznato je preko 1.400 polimorfizama pojedinačnih nukleotida [1]. Mogu se očitovati u promjenama na iRNK, spajanju ili u proteinima (npr. Arg471Cys,[14] Arg482Gln,[15] Arg527Leu,[11] Arg527Cys,[16] Ala529Val [17] ) level.

Oštećenje DNK

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Oštećenja DNK mogu se popraviti ili homologmom rekombinacijom (HR) ili nehomolognim spajanjem krajeva (NHEJ). LMNA promovira genetičku stabilnost, održavanjem nivoa proteina koji imaju ključne uloge u HR i NHEJ.[18][19] Mišje ćelije kojima nedostaje sazrijevanje prelamina A povećavaju oštećenja DNK i aberacije hromosoma i pokazuju povećanu osjetljivost na agense koji oštećuju DNK.[20] U progeriji, neadekvatnost popravka DNK, zbog neispravnog LMNA, može uzrokovati obilježja preranog starenja (vidi teorija starenja oštećenjem DNK)

Interakcije

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Pokazano je da LMNA ima interakcije sa:

Reference

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000160789 - Ensembl, maj 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000028063 - Ensembl, maj 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): 16321–6. PMID 8344919.
  6. ^ Kamat AK, Rocchi M, Smith DI, Miller OJ (mart 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.
  7. ^ Wydner KL, McNeil JA, Lin F, Worman HJ, Lawrence JB (mart 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, K. R.; Dingal, P. C.; Athirasala, A.; Kao, Y. R.; Cho, S.; Harada, T.; Shin, J. W.; Discher, D. E. (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. 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. ^ a b 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 (decembar 2006). "Human laminopathies: nuclei gone genetically awry". Nat. Rev. Genet. 7 (12): 940–52. doi:10.1038/nrg1906. PMID 17139325.
  13. ^ Rankin J, Ellard S (oktobar 2006). "The laminopathies: a clinical review". Clin. Genet. 70 (4): 261–74. doi:10.1111/j.1399-0004.2006.00677.x. PMID 16965317.
  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.
  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. ^ 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.
  17. ^ 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.
  18. ^ 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.
  19. ^ 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.
  20. ^ 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.
  21. ^ Tang K, Finley RL, Nie D, Honn KV (mart 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.
  22. ^ Wilkinson FL, Holaska JM, Zhang Z, Sharma A, Manilal S, Holt I, Stamm S, Wilson KL, Morris GE (juni 2003). "Emerin interacts in vitro with the splicing-associated factor, YT521-B" (PDF). Eur. J. Biochem. 270 (11): 2459–66. doi:10.1046/j.1432-1033.2003.03617.x. PMID 12755701. Arhivirano s originala (PDF), 16. 2. 2020. Pristupljeno 5. 3. 2021.
  23. ^ 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.
  24. ^ Sakaki M, Koike H, Takahashi N, Sasagawa N, Tomioka S, Arahata K, Ishiura S (februar 2001). "Interaction between emerin and nuclear lamins". J. Biochem. 129 (2): 321–7. doi:10.1093/oxfordjournals.jbchem.a002860. PMID 11173535.
  25. ^ Clements L, Manilal S, Love DR, Morris GE (januar 2000). "Direct interaction between emerin and lamin A". Biochem. Biophys. Res. Commun. 267 (3): 709–14. doi:10.1006/bbrc.1999.2023. PMID 10673356.
  26. ^ Barton RM, Worman HJ (oktobar 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.
  27. ^ 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.
  28. ^ Markiewicz E, Dechat T, Foisner R, Quinlan RA, Hutchison CJ (decembar 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.
  29. ^ Dechat T, Korbei B, Vaughan OA, Vlcek S, Hutchison CJ, Foisner R (oktobar 2000). "Lamina-associated polypeptide 2alpha binds intranuclear A-type lamins". J. Cell Sci. 113 (19): 3473–84. PMID 10984438.
  30. ^ Dreuillet C, Tillit J, Kress M, Ernoult-Lange M (novembar 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.
  31. ^ 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.

Dopunska literatura

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Vanjski linkovi

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