Ca(2+)-dependent protein switches in actomyosin based contractile systems

Abstract

Myosin is an ATPase enzyme with the unique property that the hydrolysis and release of Pi and ADP is coupled to movement via a cyclic interaction between myosin and actin filaments. Recent evidence indicates that for all myosin and myosin-like molecules, from slime mould and spinach vacuole to man, the mechanism of the molecular motor is essentially the same. It is now appropriate to ask general questions about how these motors are regulated by Ca2+. Is regulation the same throughout nature or are there different proteins in different phyla independently evolved? It is possible to define two basic mechanisms. Myosin may be regulated by EF hand Ca2+ binding proteins interacting with the regulatory domain or the thin filament activity may be regulated by accessory proteins. In this review I have analysed examples of myosin and actin-linked regulatory systems in order to determine the basic principles of the mechanism of these protein switches. I propose three principles common to all myosin-linked regulatory systems: (1) the regulatory proteins inhibit the cycling of a constitutively active myosin motor domain; (2) a regulatory domain in the myosin molecule has several special motifs ("IQ motif") which form binding sites for regulatory proteins; and (3) the regulatory proteins bound to the heavy chain are "EF hand" proteins related to calmodulin. I also propose a common set of principles for actin-linked regulatory systems: (1) the actin filament is normally capable of interacting with myosin to produce movement and the regulatory proteins inhibit the interaction; (2) inhibitory proteins are controlled by interaction with Ca(2+)-binding "EF hand" proteins; and (3) regulation is cooperative; the inhibitory proteins act as allosteric effectors of actin-tropomyosin state. The elongated tropomyosin propagates signals over many actins. It seems likely that myosin-linked regulation is of ancient origin. The origin of thin filament regulation is not clear. Such regulation has only been detected in animals but tropomyosin, which is a prerequisite for thin filament based regulation, is also found in protozoa and fungi, perhaps even in plants.