A new model of cooperative myosin-thin filament binding

Cooperative myosin binding to the thin filament is critical to regulation o f cardiac and skeletal muscle contraction. This report delineates and fits to experimental data a new model of this process, in which specific tropomy osin-actin interactions are important, the tropomyosin-tropomyosin polymer is continuous rather than disjointed, and tropomyosin affects myosin-actin binding by shifting among three positions as in recent structural studies. A myosin- and tropomyosin-induced conformational change in actin is propose d, rationalizing the similar to 10,000-fold strengthening effect of myosin on tropomyosin-actin binding. Also, myosin S1 binding to regulated filament s containing mutant tropomyosins with internal deletions exhibited exaggera ted cooperativity, implying an allosteric effect of tropomyosin on actin an d allowing the effect's measurement. Comparisons among the mutants suggest the change in actin is promoted much more strongly by the middle of tropomy osin than by its ends. Regardless of calcium binding to troponin, this chan ge in actin facilitates the shift in tropomyosin position to the actin inne r domain, which is required for tight myosin-actin association. It also inc reases myosin-actin affinity 7-fold compared with the absence of troponin-t ropomyosin, Finally, initiation of a shift in tropomyosin position is 100-f old more difficult than is its extension from one actin to the next, produc ing the myosin binding cooperativity that underlies cooperative activation of muscle contraction.