the r403q myosin mutation implicated in familial hypertrophic cardiomyopathy causes disorder at the actomyosin interfacer403q肌凝蛋白突变与家族性肥厚性心肌病导致障碍的肌动球蛋白接口.pdfVIP

The R403Q Myosin Mutation Implicated in Familial Hypertrophic Cardiomyopathy Causes Disorder at the Actomyosin Interface 1 1 1 2 2 1 Niels Volkmann , HongJun Lui , Larnele Hazelwood , Kathleen M. Trybus , Susan Lowey *, Dorit Hanein * 1 Burnham Institute for Medical Research, La Jolla, California, United States of America, 2 Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont, United States of America 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 b-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. Principal Findings. 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 b-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. Significance. These results provide structural