Troponin Revealed: Uncovering the Structure of the Thin Filament On-Off Switch in Striated Muscle.

Larry S Tobacman

Biophysical journal 2021 Jan 05

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Recently, our understanding of the structural basis of troponin-tropomyosin's Ca2+-triggered regulation of striated muscle contraction has advanced greatly, particularly via cryo-electron microscopy data. Compelling atomic models of troponin-tropomyosin-actin were published for both apo- and Ca2+-saturated states of the cardiac thin filament. Subsequent electron microscopy and computational analyses have supported and further elaborated the findings. Per cryo-electron microscopy, each troponin is highly extended and contacts both tropomyosin strands, which lie on opposite sides of the actin filament. In the apo-state characteristic of relaxed muscle, troponin and tropomyosin hinder strong myosin-actin binding in several different ways, apparently barricading the actin more substantially than does tropomyosin alone. The troponin core domain, the C-terminal third of TnI, and tropomyosin under the influence of a 64-residue helix of TnT located at the overlap of adjacent tropomyosins are all in positions that would hinder strong myosin binding to actin. In the Ca2+-saturated state, the TnI C-terminus dissociates from actin and binds in part to TnC; the core domain pivots significantly; the N-lobe of TnC binds specifically to actin and tropomyosin; and tropomyosin rotates partially away from myosin's binding site on actin. At the overlap domain, Ca2+ causes much less tropomyosin movement, so a more inhibitory orientation persists. In the myosin-saturated state of the thin filament, there is a large additional shift in tropomyosin, with molecular interactions now identified between tropomyosin and both actin and myosin. A new era has arrived for investigation of the thin filament and for functional understandings that increasingly accommodate the recent structural results. Copyright © 2020 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Citation

Larry S Tobacman. Troponin Revealed: Uncovering the Structure of the Thin Filament On-Off Switch in Striated Muscle. Biophysical journal. 2021 Jan 05;120(1):1-9