A general property of striated muscles, particularly rhythmically beating cardiac and fibrillar insect flight muscles, is a delayed tension rise following a rapid stretch, a phenomenon known as stretch activation. The mechanism of stretch activation remains poorly understood. Proposed hypotheses include a periodic match and mismatch between myosin origins and actin targets, changes to thin filament structure via direct connections to the thick filaments, or changes in the thick filament structure via connections to the Z-disk. Stretch activation is highly refined in the large waterbugs of the Lethocerus species. The cryoEM structure of relaxed Lethocerus thick filaments shows myosin heads adopting the interacting head motif (IHM) first seen in smooth muscle myosin. However, the IHM position differs from previously described relaxed thick filaments by the absence of nearest-neighbor contacts between IHMs; each IHM is a free-standing structure positioned so that myosin’s actin-binding region points away from actin and myosin’s SH3 domain is closest to the thin filament. The thick filament backbone is revealed in unprecedented detail and is distinguished by the presence of extra proteins threading their way among the myosin rods. We hypothesize the extra proteins loosen the rod packing density. Unfortunately, there are no other high-resolution structures of coiled-coils of this length for comparison. Formation of the IHM is correlated with filament instability in non-muscle and smooth muscle filaments. Tama et al. (J Mol. Biol. 345, 837 (2005)) modeled the effect on the coiled-coil rod domain of IHM formation. The modeled head motion toward the IHM distorted the coiled-coil rod, a property that would suggest loosening of the myosin rod packing and destabilization of the filaments. The distortion of the rod depended on the length of the rod suggesting that torsional motions of the rod α-helices are the underlying principle. Here we reverse that logic, and suggest that the low density of nearest neighbor contacts between IHMs, loose myosin rod packing, and the presence of proteins separating the myosin rods serve to poise the IHM on the edge of stability, sensitizing it to stretching of the myosin filament that could alter the rod structure. The attraction of this mechanism is simultaneous activation of all heads and continued activation until tension drops. Supported by NIH and AHA.

Implications of the interaction between myosin heads in relaxed Lethocerus asynchronous flight muscle for stretch activation

251st National Meeting (2016)

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