Contraction of muscle involves the cyclic interaction of myosin heads on the thick filaments with actin subunits in the thin filaments1. Muscles relax when this interaction is blocked by molecular switches on either or both filaments2. Insight into the relaxed (switched OFF) structure of myosin has come from electron microscopic studies of smooth muscle myosin molecules, which are regulated by phosphorylation. These studies suggest that the OFF state is achieved by an asymmetric, intramolecular interaction between the actin-binding region of one head and the converter region of the other, switching both heads off3. Although this is a plausible model for relaxation based on isolated myosin molecules, it does not reveal whether this structure is present in native myosin filaments. Here we analyse the structure of a phosphorylation-regulated striated muscle thick filament using cryo-electron microscopy. Three-dimensional reconstruction and atomic fitting studies suggest that the ‘interacting-head’ structure is also present in the filament, and that it may underlie the relaxed state of thick filaments in both smooth and myosin-regulated striated muscles over a wide range of species.
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We thank R. Horowitz, W. Lehman and A. Pirani for their help in this work. Support was provided by grants from the National Institutes of Health to R.C. and to E.H.E., an International Research Scholar grant from the Howard Hughes Medical Institute to R.P. and a grant from the National Fund for Science, Technology and Innovation (FONACIT, MCT) to R.P. Electron microscopy was carried out in the Core Electron Microscopy Facility of the University of Massachusetts Medical School, supported in part by grants from the NIH. Molecular graphics images were produced using the UCSF Chimera package from the Computer Graphics Laboratory, University of California, San Francisco, supported by a grant from the NIH.
Movie of longitudinal view of reconstruction rotated around long axis of filament (cf. Fig. 1c of paper).
Movie showing how longitudinal view of reconstruction transforms into transverse view seen in Fig. 2a of paper.
This movie shows how portions of different crowns contribute to the transverse view of the reconstruction containing a single 14.5 nm repeat seen in Fig. 2a of paper.
This movie provides a three-dimensional perspective on the fitting of the modified smooth muscle HMM atomic structure into the J-motif of the filament reconstruction (cf. Fig. 3a of paper).
This movie shows different views of the space filling atomic model of PDB 1i84 after modification to fit the "J" motif of the reconstruction (cf. Figs 3b and 5a of paper).
Movie showing how S2 fits into the reconstruction (cf. Fig. 4 of paper).