Tropomyosin and the Steric Mechanism of Muscle Regulation

Department of Physiology and Biophysics, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118, USA.
Advances in Experimental Medicine and Biology (Impact Factor: 1.96). 02/2008; 644:95-109. DOI: 10.1007/978-0-387-85766-4_8
Source: PubMed


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.

3 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tropomyosin is a major regulatory protein of contractile systems and cytoskeleton, an actin-binding protein that positions laterally along actin filaments and modulates actin-myosin interaction. About 40 tropomyosin isoforms have been found in a variety of cytoskeleton systems, not necessarily connected with actin-myosin interaction and contraction. Involvement of specific tropomyosin isoforms in the regulation of key cell processes was shown, and specific features of tropomyosin genes and protein structure have been investigated with molecular biology and genetics approaches. However, the mechanisms underlying the effects of tropomyosin on cytoskeleton dynamics are still unclear. As tropomyosin is primarily an F-actin-binding protein, it is important to understand how it interacts both with actin and actin-binding proteins functioning in muscles and cytoskeleton to regulate actin dynamics. This review focuses on biochemical data on the effects of tropomyosin on actin assembly and dynamics, as well as on the modulation of these effects by actin-binding proteins. The data indicate that tropomyosin can efficiently regulate actin dynamics via allosteric conformational changes within actin filaments. Copyright © 2015 Elsevier Inc. All rights reserved.
    International review of cell and molecular biology 08/2015; 318:255-91. DOI:10.1016/bs.ircmb.2015.06.002 · 3.42 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tropomyosin (Tpm) isoforms are the master regulators of the functions of individual actin filaments in fungi and metazoans. Tpms are coiled-coil parallel dimers that form a head-to-tail polymer along the length of actin filaments. Yeast only has two Tpm isoforms, whereas mammals have over 40. Each cytoskeletal actin filament contains a homopolymer of Tpm homodimers, resulting in a filament of uniform Tpm composition along its length. Evidence for this 'master regulator' role is based on four core sets of observation. First, spatially and functionally distinct actin filaments contain different Tpm isoforms, and recent data suggest that members of the formin family of actin filament nucleators can specify which Tpm isoform is added to the growing actin filament. Second, Tpms regulate whole-organism physiology in terms of morphogenesis, cell proliferation, vesicle trafficking, biomechanics, glucose metabolism and organ size in an isoform-specific manner. Third, Tpms achieve these functional outputs by regulating the interaction of actin filaments with myosin motors and actin-binding proteins in an isoform-specific manner. Last, the assembly of complex structures, such as stress fibers and podosomes involves the collaboration of multiple types of actin filament specified by their Tpm composition. This allows the cell to specify actin filament function in time and space by simply specifying their Tpm isoform composition. © 2015. Published by The Company of Biologists Ltd.
    Journal of Cell Science 08/2015; 128(16). DOI:10.1242/jcs.172502 · 5.43 Impact Factor
  • Source
    • "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.
    PeerJ 10/2013; 1(1):e181. DOI:10.7717/peerj.181 · 2.11 Impact Factor
Show more