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lamin-A/C; 70 kD lamin; renal carcinoma antigen NY-REN-32 (LMNA, LMN1)

Function: - lamins are components of the nuclear lamina - lamin A & lamin C filaments cross-link into an orthogonal lattice (nuclear lamina), which is attached via lamin B to the inner nuclear membrane through interactions with a lamin B receptor - lamin A & C are present in equal amounts in the nuclear lamina of mammals - proteolytic cleavage of the C-terminal of 18 residues of prelamin-A/C results in the production of lamin-A/C - the prelamin- A/C maturation pathway includes farnesylation of CAAX motif, ZMPSTE24/FACE1 mediated cleavage of the last three amino acids, methylation of the C-terminal Cys & endoproteolytic removal of the last 15 C-terminal amino acids - proteolytic cleavage of prelamin-A/C requires prior farnesylation & methylation - sumoylation is necessary for the localization to the nuclear envelope - farnesylation of prelamin-A/C facilitates nuclear envelope targeting - role in nuclear assembly, chromatin organization, nuclear membrane & telomere dynamics - DNA binding to heterochromatin [3] - increased phosphorylation of the lamins occurs before envelope disintegration & probably plays a role in regulating lamin associations - interacts with lamin- associated polypeptides IA, IB & TMPO-alpha, RB1 & with emerin - interacts with SREBF1, SREBF2, SUN2 & TMEM43 - proteolytically processed isoform A interacts with NARF - interacts with SUN1 - prelamin-A/C interacts with EMD - interacts with MLIP - interactions may regulate MLIP localization to the nuclear envelope - interacts with DMPK interaction may regulate nuclear envelope stability - interacts with: [3] a) MAK2 protein b) sterol regulatory element binding protein 1 c) splicing-associated factor Yt521-b Structure: - homodimer of lamin A & lamin C (sort of) - belongs to the intermediate filament family Compartment: - nuclear lamina (inner nuclear membrane), nuclear matrix - farnesylation of prelamin-A/C facilitates nuclear envelope targeting - subsequent cleaveage by ZMPSTE24/FACE1 to remove the farnesyl group produces mature lamin-A/C, which can then be inserted into the nuclear lamina - EMD is required for proper localization of non-farnesylated prelamin-A/C Alternative splicing: - named isoforms=3; lamin A; lamin C; Adelta10 Pathology: - defects in lmna are associated with premature aging syndromes [4] - prelamin-A/C can accelerate smooth muscle cell senescence - acts to disrupt mitosis & induce DNA damage in vascular smooth muscle cells, leading to mitotic failure, genomic instability, & premature senescence - in arteries, prelamin-A/C accumulation is not observed in young healthy vessels but is prevalent in medial vascular smooth muscle cells from aged individuals & in atherosclerotic lesions, where it often colocalizes with senescent & degenerate vascular smooth muscle cells - prelamin-A/C expression increases with age & disease - in normal aging, the accumulation of prelamin-A/C is caused in part by the down-regulation of ZMPSTE24/FACE1 in response to oxidative stress - defects in LMNA are a cause of a) Emery-Dreifuss muscular dystrophy type 2 (dominant) b) Emery-Dreifuss muscular dystrophy type 3 (recessive) c) dilated cardiomyopathy type 1a d) dilated cardiomyopathy with quadriceps myopathy e) familial partial lipodystrophy type 2 f) limb-girdle muscular dystrophy type 1b g) Charcot-Marie-Tooth disease type-2b1 h) Hutchinson-Gilford progeria syndrome i) familial atrial fibrillation j) Werner syndrome k) mandibuloacral dysplasia with type a lipodystrophy l) lethal tight skin contracture syndrome (restrictive dermopathy) m) tendinous calcinosis arthropathy & progeroid features n) heart-hand syndrome Slovenian type

Related

lamin A/C gene

Specific

lamin-A lamin-C progerin

General

human longevity protein lamin or nuclear lamin

Properties

SIZE: entity length = 664 aa MW = 74 kD COMPARTMENT: nuclear membrane MOTIF: MLIP interaction {1-130} MOTIF: Head {1-33} acetylation site SITE: N-TERMINUS EFFECTOR-BOUND: acetyl Thr phosphorylation site {T10} Ser phosphorylation site {S12} Ser phosphorylation site {S18} Thr phosphorylation site {T19} Ser phosphorylation site {S22} Thr phosphorylation site {T24} Rod {34-383} MOTIF: Coil 1A {34-70} Linker 1 {71-80} Coil 1B {81-218} Linker 2 {219-242} Coil 2 {243-383} threonine residue {266} Ser phosphorylation site {S277} Ser phosphorylation site {S301} aspartate residue {325} glutamate residue {330} Tail {384-664} MOTIF: Ser phosphorylation site {S390} Ser phosphorylation site {S392} Thr phosphorylation site {T394} Ser phosphorylation site {S395} Ser phosphorylation site {S398} Ser phosphorylation site {S403} Ser phosphorylation site {S404} Ser phosphorylation site {S406} Ser phosphorylation site {S407} Thr phosphorylation site {T409} Ser phosphorylation site {S414} Thr phosphorylation site {T416} nuclear translocation signal {417-422} Ser phosphorylation site {S423} Thr phosphorylation site {T424} Ser phosphorylation site {S458} Thr phosphorylation site {T496} Thr phosphorylation site {T505} Ser phosphorylation site {S507} Thr phosphorylation site {T510} Ser phosphorylation site {S571} Ser phosphorylation site {S573} Ser phosphorylation site {S628} Ser phosphorylation site {S632} Ser phosphorylation site {S636} proteolytic site {646-647} Ser phosphorylation site {S652} CaaX motif SITE: C-TERMINUS EFFECTOR-BOUND: farnesyl

Database Correlations

OMIM correlations MORBIDMAP 150330 UniProt P02545 PFAM correlations Entrez Gene 4000 Kegg hsa:4000

References

  1. Holtz D et al The caax motif of lamin a functions in conjunction with the nuclear localization signal to target assembly to the nuclear envelope. cell 59:969 1989 PMID: 2557160
  2. Glomset JA et al Prenyl proteins in eukaryotic cells: a new type of membrane anchor. TIBS 15(april):139 1990 PMID: 2187294
  3. Novelli G & d'Apice MR The strange case of the 'lumper' lamin a/c gene and human premature ageing. Trends in Mol Med 9(9):370, 2003 PMID: 13129702
  4. Pereira S et al HGPS and related premature aging disorders: from genomic identification to the first therapeutic approaches. Mech Ageing Dev. 2008 Jul-Aug;129(7-8):449-59 PMID: 18513784
  5. Liu B and Zhou Z Lamin A/C, laminopathies and premature ageing. Histol Histopathol. 2008 jun;23(6):747-63 PMID: 18366013
  6. Liu B et al Genomic instability in laminopathy-based premature aging. Nat Med. 2005 jul;11(7):780-5. epub 2005 jun 26 PMID: 15980864
  7. UniProt :accession p02545
  8. Human intermediate filament mutation database http://www.interfil.org
  9. GeneReviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=lmn