title: Atomic model of the human cardiac muscle myosin filament.
abstract: Of all the myosin filaments in muscle, the most important in terms of human health, and so far the least studied, are those in the human heart. Here we report a 3D single-particle analysis of electron micrograph images of negatively stained myosin filaments isolated from human cardiac muscle in the normal (undiseased) relaxed state. The resulting 28-Å resolution 3D reconstruction shows axial and azimuthal (no radial) myosin head perturbations within the 429-Å axial repeat, with rotations between successive 132 Å-, 148 Å-, and 149 Å-spaced crowns of heads close to 60°, 35°, and 25° (all would be 40° in an unperturbed three-stranded helix). We have defined the myosin head atomic arrangements within the three crown levels and have modeled the organization of myosin subfragment 2 and the possible locations of the 39 Å-spaced domains of titin and the cardiac isoform of myosin-binding protein-C on the surface of the myosin filament backbone. Best fits were obtained with head conformations on all crowns close to the structure of the two-headed myosin molecule of vertebrate chicken smooth muscle in the dephosphorylated relaxed state. Individual crowns show differences in head-pair tilts and subfragment 2 orientations, which, together with the observed perturbations, result in different intercrown head interactions, including one not reported before. Analysis of the interactions between the myosin heads, the cardiac isoform of myosin-binding protein-C, and titin will aid in understanding of the structural effects of mutations in these proteins known to be associated with human cardiomyopathies.
authors.affiliation: National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London W12 0NN, United Kingdom. h.al-khayat@imperial.ac.uk
authors.forename: Hind A
authors.initials: HA
authors.lastname: Al-Khayat
authors.forename: Robert W
authors.initials: RW
authors.lastname: Kensler
authors.forename: John M
authors.initials: JM
authors.lastname: Squire
authors.forename: Steven B
authors.initials: SB
authors.lastname: Marston
authors.forename: Edward P
authors.initials: EP
authors.lastname: Morris
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism; D064211:Connectin; D018360:Crystallography, X-Ray; D006801:Humans; D021621:Imaging, Three-Dimensional; D008854:Microscopy, Electron; D008958:Models, Molecular; D009124:Muscle Proteins / Q000378:metabolism; D009206:Myocardium / Q000737:chemistry* / Q000648:ultrastructure; D009210:Myofibrils / Q000737:chemistry* / Q000648:ultrastructure; D009218:Myosins / Q000737:chemistry* / Q000648:ultrastructure*; D011494:Protein Kinases / Q000378:metabolism; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D064211:Connectin; D009124:Muscle Proteins; D009218:Myosins; D011494:Protein Kinases; D000099163:Myosin Binding Protein C; C577285:TTN protein, human