Various Themes of Myosin Regulation

Abstract

Members of the myosin superfamily are actin-based molecular motors that are indispensable for cellular homeostasis. The vast functional and structural diversity of myosins accounts for the variety and complexity of the underlying allosteric regulatory mechanisms that determine the activation or inhibition of myosin motor activity and enable precise timing and spatial aspects of myosin function at the cellular level. This review focuses on the molecular basis of posttranslational regulation of eukaryotic myosins from different classes across species by allosteric intrinsic and extrinsic effectors. First, we highlight the impact of heavy and light chain phosphorylation. Second, we outline intramolecular regulatory mechanisms such as autoinhibition and subsequent activation. Third, we discuss diverse extramolecular allosteric mechanisms ranging from actin-linked regulatory mechanisms to myosin:cargo interactions. At last, we briefly outline the allosteric regulation of myosins with synthetic compounds.

Keywords: actin; cytoskeleton; inhibitor; posttranslational regulation.

Fig. 1

Basic building blocks of the myosin heavy chain: A myosin heavy chain consists of a prototypic motor domain (blue) which comprises the ATP binding site and an actin binding region, a light chain binding neck region containing multiple IQ-motifs (red), and a tail region (grey). N- and C-terminal extensions (grey dashed line) for the heavy chain are reported that may include N-terminal kinase domains, ATP-insensitive actin binding sites. Myosin light chains noncovalently associate with the myosin heavy chain to form the myosin holoenzyme. Moreover, myosin light chains stabilize and prime the neck region to competently function as a rigid lever that rotates relative to the myosin motor domain during the force generating power stroke that translocates myosin along actin [5]. Allosteric feedback mechanisms discussed in the present review target the motor domain, the neck domain and the tail region of the heavy chain and are listed below the respective domain. The N-terminal fraction of the molecule including the neck region and the associated light chains is referred to as S1. A longer fragment which additionally includes a portion of the tail domain is referred to as HMM. S1 fragments are monomeric whereas HMM fragments are dimeric. S1 is inherently active and serves as a powerful surrogate to study the transient-kinetic properties of the isolated myosin motor domain.

Fig. 2

Simplified model of the basic actomyosin ATPase cycle and the kinetic steps altered by endogenous and exogenous regulatory mechanisms. P_i release (red dashed line) and ADP release (black dashed line) are entry and exit point to states during the ATP hydrolysis cycle in which the myosin motor domain is strongly bound to actin. The fraction of time of the ATP hydrolysis cycle myosin stays attached to actin is referred to as its duty ratio. P_i- and ADP release are commonly associated with the rate-limiting steps of low and high duty ratio myosins. The release of ADP also determines the speed myosins translocate on actin. Allosteric targeting mechanisms affecting key steps in the chemomechanical cycle are indicated. Black arrows and font color indicate activation; red blunt arrows and font color indicate inhibition. The abbreviations used are as follows: M = myosin, A = actin, P_i = inorganic phosphate.

Fig. 3

Selected myosin classes, their regulatory targeting mechanisms and cellular function. It is of note that not each of the regulatory mechanisms listed is applicable to each member in a given myosin class. The reader is redirected to comprehensive reviews for the detailed physiological function of individual members of a given myosin class [3, 4]. Motors indicate the number of myosin motor domains in the minimum functional unit of the protein. The notation 1/2 indicates that the myosin is a monomer but requires dimerization to become processive. The notation 2/F indicates that class-2 myosins are dimeric but assemble into filaments under physiological conditions inside cells. The column “small molecule” includes both, myosin activators and inhibitors. Light grey color indicated that regulatory events of phosphorylation, cations, and small molecule modulators have not be reported. Abbreviations are as follows: HC: heavy chain; LC: light chain.