Mechanisms of myosin II force generation: insights from novel experimental techniques and approaches.

Abstract

Myosin II is a molecular motor that converts chemical energy derived from ATP hydrolysis into mechanical work. Myosin II isoforms are responsible for muscle contraction and a range of cell functions relying on the development of force and motion. When the motor attaches to actin, ATP is hydrolyzed and inorganic phosphate (Pi) and ADP are released from its active site. These reactions are coordinated with changes in the structure of myosin, promoting the so-called "power stroke" that causes the sliding of actin filaments. The general features of the myosin-actin interactions are well accepted, but there are critical issues that remain poorly understood, mostly due to technological limitations. In recent years, there has been a significant advance in structural, biochemical, and mechanical methods that have advanced the field considerably. New modeling approaches have also allowed researchers to understand actomyosin interactions at different levels of analysis. This paper reviews recent studies looking into the interaction between myosin II and actin filaments, which leads to power stroke and force generation. It reviews studies conducted with single myosin molecules, myosins working in filaments, muscle sarcomeres, myofibrils, and fibers. It also reviews the mathematical models that have been used to understand the mechanics of myosin II in approaches focusing on single molecules to ensembles. Finally, it includes brief sections on translational aspects, how changes in the myosin motor by mutations and/or posttranslational modifications may cause detrimental effects in diseases and aging, among other conditions, and how myosin II has become an emerging drug target.