Thin Filament Structure and the Steric Blocking Model

Abstract

By interacting with the troponin-tropomyosin complex on myofibrillar thin filaments, Ca2+ and myosin govern the regulatory switching processes influencing contractile activity of mammalian cardiac and skeletal muscles. A possible explanation of the roles played by Ca2+ and myosin emerged in the early 1970s when a compelling "steric model" began to gain traction as a likely mechanism accounting for muscle regulation. In its most simple form, the model holds that, under the control of Ca2+ binding to troponin and myosin binding to actin, tropomyosin strands running along thin filaments either block myosin-binding sites on actin when muscles are relaxed or move away from them when muscles are activated. Evidence for the steric model was initially based on interpretation of subtle changes observed in X-ray fiber diffraction patterns of intact skeletal muscle preparations. Over the past 25 years, electron microscopy coupled with three-dimensional reconstruction directly resolved thin filament organization under many experimental conditions and at increasingly higher resolution. At low-Ca2+, tropomyosin was shown to occupy a "blocked-state" position on the filament, and switched-on in a two-step process, involving first a movement of tropomyosin away from the majority of the myosin-binding site as Ca2+ binds to troponin and then a further movement to fully expose the site when small numbers of myosin heads bind to actin. In this contribution, basic information on Ca2+-regulation of muscle contraction is provided. A description is then given relating the voyage of discovery taken to arrive at the present understanding of the steric regulatory model.

Tropomodulins and Leiomodins: Actin Pointed End Caps and Nucleators in Muscles

“…As discussed below, the interacting surface of ABS2 at this site is highly conserved individually within the Tmod and Lmod subfamilies, but not across subfamilies, offering important clues about their specialized biochemical activities. Fifth, this model is consistent with the azimuthal sliding of TM on the surface of the actin filament (53,54), whereby TM can explore three structural states (blocked, closed, and open) without generating steric clashes with Tmod at the pointed end, albeit likely influenced by Tmod-TM isoform specific interactions (see below). Sixth, this model is consistent with the results of numerous mutagenesis and capping studies (5,31,38,44,55,56).…”

“…The structure of the two TM-binding sites (green) is unknown, and a tentative model was generated based on secondary structure prediction and energy minimization (5). TM is shown in the blocked state, which it assumes when bound to the filament with Ca2þ-free troponin (53,111). Of note, this model is consistent with TM's ability to explore all three states on the filament (blocked, closed, and open) (53,54), without generating steric clashes with Tmod at the pointed end.…”

Coupling between myosin head conformation and the thick filament backbone structure

“…The actin filaments from all muscles host a long protein with an α-helical coiled coil structure called tropomyosin (Clark et al, 2002). In those muscles where tension production is regulated at the thin filament, changing concentrations of calcium ions alter myosin’s access to actin via tropomyosin’s interaction with the troponin (Tn) complex, consisting of three proteins, Tn-C, Tn-T and Tn-I (Lehman, 2016). Capping proteins occur at the ends to stabilize the length (Littlefield and Fowler, 1998).…”

The Relaxation Properties of Myofibrils Are Compromised by Amino Acids that Stabilize α-Tropomyosin

“…Adjacent Tm molecules, each covering seven actin monomers and interacting with one Tn (the so-called actin 7 TmTn structural unit), bind head-to-tail and form a continuous strand along the entire length of the actin filament, blocking sites for myosin binding. When Ca 2þ binds to Tn, the Tm strand azimuthally moves and permits myosin access on actin and cross-bridge formation (1)(2)(3). The different molecular properties of Tm isoforms in vertebrate striated muscle are involved in the dynamics of Ca 2þ -induced Tm movement on actin and the highly cooperative activation of contraction (4,5).…”