title: The R403Q myosin mutation implicated in familial hypertrophic cardiomyopathy causes disorder at the actomyosin interface.
abstract: BACKGROUND
  Mutations in virtually all of the proteins comprising the cardiac muscle sarcomere have been implicated in causing Familial Hypertrophic Cardiomyopathy (FHC). Mutations in the beta-myosin heavy chain (MHC) remain among the most common causes of FHC, with the widely studied R403Q mutation resulting in an especially severe clinical prognosis. In vitro functional studies of cardiac myosin containing the R403Q mutation have revealed significant changes in enzymatic and mechanical properties compared to wild-type myosin. It has been proposed that these molecular changes must trigger events that ultimately lead to the clinical phenotype.
  
  
  RESULTS
  Here we examine the structural consequences of the R403Q mutation in a recombinant smooth muscle myosin subfragment (S1), whose kinetic features have much in common with slow beta-MHC. We obtained three-dimensional reconstructions of wild-type and R403Q smooth muscle S1 bound to actin filaments in the presence (ADP) and absence (apo) of nucleotide by electron cryomicroscopy and image analysis. We observed that the mutant S1 was attached to actin at highly variable angles compared to wild-type reconstructions, suggesting a severe disruption of the actin-myosin interaction at the interface.
  
  
  CONCLUSIONS
  These results provide structural evidence that disarray at the molecular level may be linked to the histopathological myocyte disarray characteristic of the diseased state.
authors.affiliation: Burnham Institute for Medical Research, La Jolla, California, United States of America.
authors.forename: Niels
authors.initials: N
authors.lastname: Volkmann
authors.forename: Hongjun
authors.initials: H
authors.lastname: Lui
authors.forename: Larnele
authors.initials: L
authors.lastname: Hazelwood
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Trybus
authors.forename: Susan
authors.initials: S
authors.lastname: Lowey
authors.forename: Dorit
authors.initials: D
authors.lastname: Hanein
mesh_terms: D000205:Actomyosin / Q000502:physiology*; D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics*; D002645:Chickens; D020285:Cryoelectron Microscopy; D006801:Humans; D009130:Muscle, Smooth / Q000378:metabolism; D009218:Myosins / Q000235:genetics* / Q000648:ultrastructure; D017354:Point Mutation
chemical_list: D000244:Adenosine Diphosphate; D000205:Actomyosin; D009218:Myosins