lamin-A/C; 70 kD lamin; renal carcinoma antigen NY-REN-32 (LMNA, LMN1)
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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]
- MAK2 protein
- sterol regulatory element binding protein 1
- 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
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
- Emery-Dreifuss muscular dystrophy type 2 (dominant)
- Emery-Dreifuss muscular dystrophy type 3 (recessive)
- dilated cardiomyopathy type 1a
- dilated cardiomyopathy with quadriceps myopathy
- familial partial lipodystrophy type 2
- limb-girdle muscular dystrophy type 1b
- Charcot-Marie-Tooth disease type-2b1
- Hutchinson-Gilford progeria syndrome
- familial atrial fibrillation
- Werner syndrome
- mandibuloacral dysplasia with type a lipodystrophy
- lethal tight skin contracture syndrome (restrictive dermopathy)
- tendinous calcinosis arthropathy & progeroid features
- heart-hand syndrome Slovenian type
More general terms
More specific terms
References
- ↑ 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: https://www.ncbi.nlm.nih.gov/pubmed/2557160
- ↑ Glomset JA et al Prenyl proteins in eukaryotic cells: a new type of membrane anchor. TIBS 15(april):139 1990 PMID: https://www.ncbi.nlm.nih.gov/pubmed/2187294
- ↑ 3.0 3.1 3.2 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: https://www.ncbi.nlm.nih.gov/pubmed/13129702
- ↑ 4.0 4.1 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: https://www.ncbi.nlm.nih.gov/pubmed/18513784
- ↑ Liu B and Zhou Z Lamin A/C, laminopathies and premature ageing. Histol Histopathol. 2008 jun;23(6):747-63 PMID: https://www.ncbi.nlm.nih.gov/pubmed/18366013
- ↑ Liu B et al Genomic instability in laminopathy-based premature aging. Nat Med. 2005 jul;11(7):780-5. epub 2005 jun 26 PMID: https://www.ncbi.nlm.nih.gov/pubmed/15980864
- ↑ UniProt http://www.uniprot.org/uniprot/p02545.html
- ↑ Human intermediate filament mutation database http://www.interfil.org
- ↑ GeneReviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=lmn
Database
- Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=4000
- Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:4000
- OMIM: https://mirror.omim.org/entry/115200
- OMIM: https://mirror.omim.org/entry/150330
- OMIM: https://mirror.omim.org/entry/151660
- OMIM: https://mirror.omim.org/entry/159001
- OMIM: https://mirror.omim.org/entry/176670
- OMIM: https://mirror.omim.org/entry/181350
- OMIM: https://mirror.omim.org/entry/212112
- OMIM: https://mirror.omim.org/entry/248370
- OMIM: https://mirror.omim.org/entry/275210
- OMIM: https://mirror.omim.org/entry/605588
- OMIM: https://mirror.omim.org/entry/610140
- OMIM: https://mirror.omim.org/entry/613205
- UniProt: http://www.uniprot.org/uniprot/P02545.html