The Sliding Filament Model: 1972–2004

This review will describe the investigation of the mechanism of muscle contraction and cell motility from 1972 to the present. The preceding article in this issue by Andrew Szent-Gyorgyi covers the period up to 1972. In 1972 the field of actomyosin interactions was summarized in a conference at Cold Spring Harbor, published in the Cold Spring Harbor Symposia on Quantitative Biology XXXVII, 1973. After this meeting many participants thought that the problem of muscle contraction was solved “in principle”. In many ways this attitude was correct. In the mid-1950s it had been established that during muscle contraction two sets of filaments of constant length slide past each other. Prior to the sliding filament model, the most popular theories held that contraction was produced by the shortening of some large, rubber-like polymers. Since 1954, the motor that produced filament sliding, the myosin head, had been observed both by electron microscopy and X-ray diffraction. Kinetics studies had shown that ATP dissociated actin from myosin and that ATP was hydrolyzed when myosin was detached from actin leading to a four-state model of the kinetics of the actin myosin interaction. The synthesis of these results led to a model of myosin action in which a rigid myosin head attached to actin and changed its orientation producing the power stroke before being detached. This simple elegant model was able to explain much of the existing data on the interaction of myosin with actin in muscle and in solution. Although the model proposed in 1972 was in essence correct, there was in fact a long road ahead leading to the present level of understanding of the motor proteins. Major milestones on this road include solving the three-dimensional structures of the actin monomer and the myosin head in a number of their different nucleotide states. The structural information was synthesized with, unthinkable in 1972, measurements of the mechanics of single myosin molecules. This development was facilitated by the demonstration that the muscle myosin, studied so intensely in 1972, is in fact only one member of a large superfamily of myosin molecules, some of which were more amenable to study by biophysical techniques. Genetically engineered proteins provided novel preparations for enzymatic and structural studies. In addition an entirely new super family of microtubule motors was discovered. This review will describe these studies leading to our current models of force production by motor proteins in eukaryotic cells. Due to the limitations of length, the review will not be comprehensive, but will concentrate on some of the key experiments leading to our understanding of force production by the two motor proteins, myosin and kinesin. An excellent book covers much of this material (Howard, 2001).