The Actomyosin Cross Bridge Cycle


The cross bridge cycle can be described as a series of coupled biochemical and mechanical events. The efficient conversion of biochemical energy requires a very precise temporal coupling between the biochemical and mechanical events - the structure of the myosin head is presumably designed to achieve this end. The cross bridge cycle for fast skeletal muscle is the most thoroughly studied system and the description of the cycle that follows refers to this actomyosin. The basic cycle is believed to be the same for all myosins, but the relative rates of individual steps are altered by changes in the amino acid sequence of myosin to tune each myosin for its particular physiological role. Comparisons of the properties of different myosins, together with mutagenesis of specific amino acid residues or of short sequences, are the most active areas of current research.





The essential mechanochemical steps are shown lettered a to e. ATP binding to either a resting length myosin head (c) or to a head bearing a load (b) results a change in conformation in the myosin head, causing a rapid, almost irreversible dissociation of the myosin head from actin (d). Following detachment from actin, the ATP is hydrolysed to ADP and Pi, both of which remain very tightly bound to the myosin head (e). The hydrolysis is relatively rapid (taking about about 10 msec) and reversible (Keq = 10). The small value of the Keq indicates that the free energy of ATP hydrolysis is not released but remains within the structure of the M.ADP.Pi complex. The crystal structures of myosin heads with bound nucleotides or nucleotide analogues are believed to represent one or the other of these two structures (d & e). This suggests that the hydrolysis is accompanied by a major conformational change which represents the reversal or a repriming of the power stroke. Structures d & e are quite stable and ADP and Pi will remain bound to the myosin head until the myosin binds to an actin site. The affinity of M.ADP.Pi for actin is significantly higher than that of M.ATP. If an actin site is within reach of the myosin head, it will bind rapidly and reversibly to the actin site. In doing so, it can explore several potential actin binding sites. Current opinion suggests that the majority (>80%) of myosin heads within an active isometric (not shortening) muscle are in equilibrium between states a, d & e.


When the myosin head binds actin the interaction with actin can promote a major change in conformation (the power stroke) which is accompanied by the dissociation of Pi. Crystal structures suggest that the power stroke consists of a reorientation of part of the myosin head distal to the actin-binding site and includes the 'converter' region and the light chain-binding domain (LCBD). This results in the displacement of the tip of the LCBD by up to 10 nm. The structural changes in the actin-myosin interface that produce the power stroke remain undefined.


If the filaments carry an external load then the power stroke results in the distortion of an elastic element (b). The location and nature of the elastic element is unknown but may represent a distortion in the myosin head or of the LCBD. For simplicity, the elastic element is drawn here as part of the connection between the myosin head and the thick filament. While the myosin head carries a load and is elastically distorted, the dissociation of Pi is a reversible event and Pi can rebind to reverse the power stroke (and also go back through intermediates e & d).


If the external load is small, then the power stroke results in the relative sliding of the actin and myosin filaments by a distance of up to 10 nm. Following the sliding, ADP is released very quickly (within 2 msec) to be replaced within a msec by ATP, and the myosin head dissociates once more to complete the cycle. The final element of the mechanochemical coupling is believed to be a mechanism to limit the rate of release of ADP until the sliding motion is complete. Thus ADP release from b is much slower than from c. The mechanism of the strain-limited ADP release is currently under investigation, but appears to be a key event which differs between myosins designed for efficient fast shortening vs efficient load bearing. The structural changes observed on binding ADP to smooth actomyosin and BBMI might reflect this strain-sensing mechanism.






Contributed by Mike Geeves, University of Kent

Figure and movie by Stefan Weiss & Mike Geeves 1999


Recent Review
Geeves, M.A. & Holmes, K.C. 1999 Structural mechanism of muscle contraction. Ann. Rev. Biochem. 68, 687-728.



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