Structure of the lamin A/C R482W mutant responsible for dominant familial partial lipodystrophy (FPLD).
Proteins of the A-type lamin family, which consists of two members, lamin A and lamin C, are the major components of a thin proteinaceous filamentous meshwork, the lamina, that underlies the inner nuclear membrane. A-type lamins have recently become the focus of extensive functional studies as a consequence of the linking of at least eight congenital diseases to mutations in the lamin A/C gene (LMNA). This spectrum of pathologies, which mostly manifest themselves as dominant traits, includes muscle dystrophies, dilated cardiomyopathies, the premature aging syndrome Hutchinson-Guilford progeria and familial partial lipodystrophy (FPLD). The crystal structure of the lamin A/C mutant R482W, a variant that causes FPLD, has been determined at 1.5 A resolution. A completely novel aggregation state of the C-terminal globular domain and the position of the mutated amino-acid residue suggest means by which the mutation may affect lamin A/C-protein and protein-DNA interactions.
Magracheva
Eugenia
E
Basic Research Program SAIC-Frederick, NCI-Frederick, Frederick, MD 21702, USA.
Kozlov
Serguei
S
Stewart
Colin L
CL
Wlodawer
Alexander
A
Zdanov
Alexander
A
D000494:Allosteric Regulation; D019943:Amino Acid Substitution / Q000235:genetics; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism; D005799:Genes, Dominant; D006801:Humans; D034904:Lamin Type A / Q000737:chemistry* / Q000235:genetics*; D052496:Lipodystrophy, Familial Partial / Q000235:genetics*; D050505:Mutant Proteins / Q000737:chemistry* / Q000235:genetics; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D055672:Static Electricity
D034904:Lamin Type A; D050505:Mutant Proteins; C440308:lamin C; D004247:DNA