title: Structural interpretation of the mutations in the beta-cardiac myosin that have been implicated in familial hypertrophic cardiomyopathy.
abstract: In 10-30% of hypertrophic cardiomyopathy kindreds, the disease is caused by > 29 missense mutations in the cardiac beta-myosin heavy chain (MYH7) gene. The amino acid sequence similarity between chicken skeletal muscle and human beta-cardiac myosin and the three-dimensional structure of the chicken skeletal muscle myosin head have provided the opportunity to examine the structural consequences of these naturally occurring mutations in human beta-cardiac myosin. This study demonstrates that the mutations are related to distinct structural and functional domains. Twenty-four are clustered around four specific locations in the myosin head that are (i) associated with the actin binding interface, (ii) around the nucleotide binding site, (iii) adjacent to the region that connects the two reactive cysteine residues, and (iv) in close proximity to the interface of the heavy chain with the essential light chain. The remaining five mutations are in the myosin rod. The locations of these mutations provide insight into the way they impair the functioning of this molecular motor and also into the mechanism of energy transduction.
authors.affiliation: Institute for Enzyme Research, Graduate School, University of Wisconsin, Madison 53705-4098, USA.
authors.forename: I
authors.initials: I
authors.lastname: Rayment
authors.forename: H M
authors.initials: HM
authors.lastname: Holden
authors.forename: J R
authors.initials: JR
authors.lastname: Sellers
authors.forename: L
authors.initials: L
authors.lastname: Fananapazir
authors.forename: N D
authors.initials: ND
authors.lastname: Epstein
mesh_terms: D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics*; D002645:Chickens; D003545:Cysteine; D006801:Humans; D008958:Models, Molecular; D009206:Myocardium / Q000378:metabolism*; D009218:Myosins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry; D017354:Point Mutation; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D014357:Trypsin
chemical_list: D000199:Actins; D010446:Peptide Fragments; D014357:Trypsin; D009218:Myosins; D003545:Cysteine