Common Structural Motifs for the Regulation of Divergent Class II Myosins

Abstract

This minireview focuses on structural studies that have provided insights into our current understanding of thick filament regulation in muscle. We describe how different domains in the myosin molecule interact to produce an inactive "off" state; included are head-head and head-rod interactions, the role of the regulatory light chain, and the significance of the ␣-helical coiled-coil rod in regulation. Several of these interactions have now been visualized in a wide variety of native myosin filaments, testifying to the generality of these structural motifs across the phylogenetic tree.The publication of the crystal structure of the globular head region of skeletal muscle myosin (subfragment 1 (S1)3 ) in 1993 (1) made it possible for the first time to understand how biological motors function at the atomic level (Fig. 1, A and B). By fitting, the S1 head structure into macromolecular complexes of actin filaments decorated with S1, Rayment et al. (2) were able to propose the first detailed mechanism for the generation of force and movement in motile cells. This exciting new structural framework, together with impressive advances in determining the displacement and force produced by a single molecular motor, inspired a Biophysical Discussions meeting in 1994. We discussed the role of the light chains in the so-called "lever arm" of the myosin head (3). Here, we summarize some of the major developments in the regulation of class II myosins in the intervening 15 years.

Calmodulin Bound to the First IQ Motif Is Responsible for Calcium-dependent Regulation of Myosin 5a

“…Several groups identified the specific IQ motif to be the second IQ motif (IQ2) and proposed that Ca 2ϩ -dependent regulation of myosin 5a is via the CaM in IQ2 (13)(14)(15)(16). This hypothesis seems plausible since the regulation of scallop myosin and smooth muscle myosin is initiated from the regulatory light chain (a CaM-like light chain) bound to IQ2 (17)(18)(19). However, there is no direct evidence to support this hypothesis.…”

Regulation of the actin-activated MgATPase activity ofAcanthamoebamyosin II by phosphorylation of serine 639 in motor domain loop 2

“…Although the structure of AMII is similar to that of other class II myosins, regulation of the actin-activated ATPase activity of AMII differs from the known regulatory mechanisms of other myosin IIs (7). Striated (skeletal and cardiac) muscle myosin IIs are activated by Ca 2+ -binding to the tropomyosin/troponin complex associated with the actin filament; vertebrate smooth muscle and nonmuscle myosin IIs and Dictyostelium myosin II filaments are activated by Ca 2+ -activated kinase phosphorylation of the regulatory light chain; and molluscan muscle myosin II is activated by Ca 2+ -binding to the essential light chain.…”

“…Furthermore, we found that, in addition to the previously identified phosphorylated serines in the nonhelical tailpiece, Ser639 also is phosphorylated in enzymatically inactive endogenous AMII purified from amoebae, and pSer639 is dephosphorylated in phosphatase-treated, enzymatically active AMII. To our knowledge, this is the first example of the regulation of any myosin by covalent modification of any amino acid in loop 2 (7,23). The effects of phosphorylation of Ser639 and serines in the nonhelical tailpiece on the structure of AMII filaments are described in the accompanying paper (22).…”

Signaling through Myosin Light Chain Kinase in Smooth Muscles

“…The myosin II subfamily members, including smooth muscle myosin, are hexamers composed of heavy chain dimers and two pairs of myosin light chains (1,2). The heavy chain motor domain binds reversibly to actin filaments, hydrolyzes ATP, and thereby converts chemical energy into mechanical force and movement.…”

“…Myosin light chain phosphatase dephosphorylates RLC to induce relaxation. RLC phosphorylation drives diverse cellular movements such as cell division, cell migration, and cell-matrix adhesion as well as smooth muscle contraction (1,2,6,7).…”