Contraction in all muscles must be precisely regulated and requisite control systems must be able to adjust to changes in physiological and myopathic stimuli. In this chapter, we outline the structural evidence for a steric mechanism that governs muscle activity. The mechanism involves calcium and myosin induced changes in the position of tropomyosin along actin-based thin filaments. This process either blocks or uncovers myosin crossbridge binding sites on actin and consequently regulates crossbridge cycling on thin filaments, the sliding of thin and thick filaments and muscle shortening and force production.
"weak myosin binding (closed state) that promotes the strong myosin binding (open state) leading to force development. The three regulatory states are in rapid equilibrium with one another, where any one state may dominate depending on the influence of troponin and myosin (Bremel and Weber, 1972; McKillop and Geeves, 1993; Maytum et al., 1999; Lehrer and Geeves, 1998; Lehman and Craig, 2008). This regulation involves cooperative and allosteric interactions among the protein components, with actin being the catalytic subunit, while tropomyosin is the regulatory component, and troponin in the absence and presence of Ca 2þ is the allosteric inhibitor and activator, respectively. "
"The contraction of these striated muscles involves the synchronized movement of myosin heads that are engaged with actin filaments to produce a net translocation of the myosin thick filament with respect to the actin thin filament (Geeves, 2012; Lehrer and Geeves, 2014). The actin thin filament is composed of three core elements: a double-stranded polymer of actin, two continuous polymers of Tpm running along each side of the actin and the troponin complex, a heteromeric protein complex consisting of troponin T (TnT), troponin I (TnI) and troponin C (TnC), which is located on each Tpm dimer (Lehman and Craig, 2008). In response to a pulse of Ca 2+ the troponin complex moves the position of the Tpm polymer to facilitate the coordinated engagement of the heads of the myosins in the thick filament with actins in the thin filament. "
"Strong binding of myosin heads (S1) to the filament increases affinity of TM to actin and induces an azimuthal shift of TM chains. This changes the TM interactions with actin and activates the filament allowing for actin–myosin cross-bridge cycling (Lehman & Craig, 2008; Moraczewska, 2002). Saturation of the filament with myosin S1 caused a significant increase of the fluorescence of AEDANS bound to C-terminal segments of all studied TM isoforms. "
[Show abstract][Hide abstract] ABSTRACT: Tropomyosins are actin-binding regulatory proteins which overlap end-to-end along the filament. High resolution structures of the overlap regions were determined for muscle and non-muscle tropomyosins in the absence of actin. Conformations of the junction regions bound to actin are unknown. In this work, orientation of the overlap on actin alone and on actin-myosin complex was evaluated by measuring FRET distances between a donor (AEDANS) attached to tropomyosin and an acceptor (DABMI) bound to actin's Cys374. Donor was attached to the Cys residue introduced by site-directed mutagenesis near the C-terminal half of the overlap. The recombinant alpha-tropomyosin isoforms used in this study - skeletal muscle skTM, non-muscle TM2 and TM5a, and chimeric TM1b9a had various amino acid sequences of the N- and C-termini involved in the end-to-end overlap. The donor-acceptor distances calculated for each isoform varied between 36.4 Å and 48.1 Å. Rigor binding of myosin S1 increased the apparent FRET distances of skTM and TM2, but decreased the distances separating TM5a and TM1b9a from actin. The results show that isoform-specific sequences of the end-to-end overlaps determine orientations and dynamics of tropomyosin isoforms on actin. This can be important for specificity of tropomyosin in the regulation of actin filament diverse functions.
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