Abstract
The intensities of the myosin-based layer lines in the x-ray diffraction patterns from live resting frog skeletal muscles with full thick-thin filament overlap from which partial lattice sampling effects had been removed were analyzed to elucidate the configurations of myosin crossbridges around the thick filament backbone to nanometer resolution. The repeat of myosin binding protein C (C-protein) molecules on the thick filaments was determined to be 45.33 nm, slightly longer than that of myosin crossbridges. With the inclusion of structural information for C-proteins and a pre-powerstroke head shape, modeling in terms of a mixed population of regular and perturbed regions of myosin crown repeats along the filament revealed that the myosin filament had azimuthal perturbations of crossbridges in addition to axial perturbations in the perturbed region, producing pseudo-six-fold rotational symmetry in the structure projected down the filament axis. Myosin crossbridges had a different organization about the filament axis in each of the regular and perturbed regions. In the regular region that lacks C-proteins, there were inter-molecular interactions between the myosin heads in axially adjacent crown levels. In the perturbed region that contains C-proteins, in addition to inter-molecular interactions between the myosin heads in the closest adjacent crown levels, there were also intra-molecular interactions between the paired heads on the same crown level. Common features of the interactions in both regions were interactions between a portion of the 50-kDa-domain and part of the converter domain of the myosin heads, similar to those found in the phosphorylation-regulated invertebrate myosin. These interactions are primarily electrostatic and the converter domain is responsible for the head-head interactions. Thus multiple head-head interactions of myosin crossbridges also characterize the switched-off state and have an important role in the regulation or other functions of myosin in thin filament-regulated muscles as well as in the thick filament-regulated muscles.
Highlights
Muscles relax when the interaction between actin and myosin is blocked by molecular switches on either or both the thin and the thick filaments in a sarcomere which is the smallest functional and structural unit of striated muscle
Myosin filaments in smooth muscles and certain types of invertebrate striated muscles participate in the regulation of muscle contraction, the role of thick filament structure in the regulation of striated muscles of higher vertebrates, which are primarily controlled by Ca2+-binding to troponin-tropomyosin on the thin filaments, has not been clearly elucidated
Using an atomic structure of myosin molecule, these studies have revealed the structure of thick filaments to nanometer-scale resolution, suggesting that interactions between myosin heads resulting in the formation of a so-called ‘‘interacting head motif’’ are responsible for switching off the myosin molecules in vertebrate smooth muscles [3], invertebrate striated muscles with phosphorylation-dependent regulation such as tarantula [4,5] and limulus [6] muscles and in scallop muscles [7] with Ca2+dependent regulation
Summary
Muscles relax when the interaction between actin and myosin is blocked by molecular switches on either or both the thin and the thick filaments in a sarcomere which is the smallest functional and structural unit of striated muscle. Recent studies showed that similar head-head interactions of myosin crossbridges occurred in isolated thick filaments from vertebrate fish skeletal [8] and cardiac striated [9,10] muscles and in heavy meromyosin (HMM) molecules (comprising of the two heads and part of the rod) from vertebrate cardiac and skeletal muscles when they were treated with blebbistatin, a known inhibitor of actin-binding and ATPase (catalysis of the hydrolysis of adenosine triphosphate (ATP)) activity of myosin molecules, those muscles are not thought to be intrinsically regulated by the myosin molecules [11] This interacting head structure is a plausible model for relaxation based on isolated myosin filaments, it has not been clearly proved whether or not this structure occurs in the native myosin filaments in higher vertebrate muscles
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