The Ig-like structure of the C-terminal domain of lamin A/C, mutated in muscular dystrophies, cardiomyopathy, and partial lipodystrophy.
Lamins are nuclear intermediate filaments that, together with lamin-associated proteins, maintain nuclear shape and provide a structural support for chromosomes and replicating DNA. We have determined the solution structure of the human lamin A/C C-terminal globular domain which contains specific mutations causing four different heritable diseases. This domain encompasses residues 430-545 and adopts an Ig-like fold of type s. We have also characterized by NMR and circular dichroism the structure and thermostability of three mutants, R453W and R482W/Q, corresponding to "hot spots" causing Emery-Dreifuss muscular dystrophy and Dunnigan-type lipodystrophy, respectively. Our structure determination and mutant analyses clearly show that the consequences of the mutations causing muscle-specific diseases or lipodystrophy are different at the molecular level.
Krimm
Isabelle
I
Département d'Ingénierie et d'Etudes des Protéines, CEA Saclay, 91191, Gif-sur-Yvette, France.
Ostlund
Cecilia
C
Gilquin
Bernard
B
Couprie
Joël
J
Hossenlopp
Paul
P
Mornon
Jean-Paul
JP
Bonne
Gisèle
G
Courvalin
Jean-Claude
JC
Worman
Howard J
HJ
Zinn-Justin
Sophie
S
D000595:Amino Acid Sequence; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism; D002942:Circular Dichroism; D017124:Conserved Sequence; D007136:Immunoglobulins / Q000235:genetics; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism; D008060:Lipodystrophy / Q000235:genetics* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009136:Muscular Dystrophies / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein
D007136:Immunoglobulins; D034904:Lamin Type A