Cooperativity of weak actomyosin interaction

We report the discovery of a new regulatory mechanism of the actomyosin system in muscle. We show that the weak binding of the myosin-nucleotide complex with unregulated F-actin is a cooperative process. Hundreds of myosin heads must work together for efficient force production in muscle, but the precise mechanism by which they coordinate remains elusive. It is known that myosin initially binds actin weakly, then transitions into a strongly bound state to produce force. Using the contiguous cooperative binding model, we interpreted our experimental results in terms of a cooperativity parameter defined as an increased probability for a myosin head to bind to the actin filament next to the already bound head. Considering the geometric organization of a sarcomere, we propose the formation of cross-bridge clusters composed of up to six myosin heads bound consecutively to actin. The cooperativity of weak actomyosin interaction may explain several challenging questions in muscle physiology, such as the role of myosin isoforms in mixed-isoform hybrid muscles, or the yield of supramaximal rate of force production in decorated skinned muscle fibers.