The myosin mesa and the basis of hypercontractility caused by hypertrophic cardiomyopathy mutations.
Nat Struct Mol Biol
; 24(6): 525-533, 2017 Jun.
Article
en En
| MEDLINE
| ID: mdl-28481356
ABSTRACT
Hypertrophic cardiomyopathy (HCM) is primarily caused by mutations in ß-cardiac myosin and myosin-binding protein-C (MyBP-C). Changes in the contractile parameters of myosin measured so far do not explain the clinical hypercontractility caused by such mutations. We propose that hypercontractility is due to an increase in the number of myosin heads (S1) that are accessible for force production. In support of this hypothesis, we demonstrate myosin tail (S2)-dependent functional regulation of actin-activated human ß-cardiac myosin ATPase. In addition, we show that both S2 and MyBP-C bind to S1 and that phosphorylation of either S1 or MyBP-C weakens these interactions. Importantly, the S1-S2 interaction is also weakened by four myosin HCM-causing mutations but not by two other mutations. To explain these experimental results, we propose a working structural model involving multiple interactions, including those with myosin's own S2 and MyBP-C, that hold myosin in a sequestered state.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Cardiomiopatía Hipertrófica
/
Proteínas Portadoras
/
Cadenas Pesadas de Miosina
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Miosinas Cardíacas
/
Mutación
Límite:
Humans
Idioma:
En
Revista:
Nat Struct Mol Biol
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos