1. Troponin-I--induced tropomyosin pivoting defines thin-filament function in relaxed and active muscle.
- Author
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Lehman, William and Rynkiewicz, Michael J.
- Subjects
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MYOSIN , *TROPOMYOSINS , *MUSCLE contraction , *ATOMIC models , *TROPONIN , *ACTIN - Abstract
Regulation of the crossbridge cycle that drives muscle contraction involves a reconfiguration of the troponin--tropomyosin complex on actin filaments. By comparing atomic models of troponin--tropomyosin fitted to cryo-EM structures of inhibited and Ca2+-activated thin filaments, we find that tropomyosin pivots rather than rolls or slides across actin as generally thought. We propose that pivoting can account for the Ca2+ activation that initiates muscle contraction and then relaxation influenced by troponin-I (TnI). Tropomyosin is well-known to occupy either of three meta-stable configurations on actin, regulating access of myosin motorheads to their actin-binding sites and thus the crossbridge cycle. At low Ca2+ concentrations, tropomyosin is trapped by TnI in an inhibitory B-state that sterically blocks myosin binding to actin, leading to muscle relaxation. Ca2+ binding to TnC draws TnI away from tropomyosin, while tropomyosin moves to a C-state location over actin. This partially relieves the steric inhibition and allows weak binding of myosin heads to actin, which then transition to strong actin-bound configurations, fully activating the thin filament. Nevertheless, the reconfiguration that accompanies the initial Ca2+-sensitive B-state/C-state shift in troponin--tropomyosin on actin remains uncertain and at best is described by moderate-resolution cryo- EM reconstructions. Our recent computational studies indicate that intermolecular residue-to-residue salt-bridge linkage between actin and tropomyosin is indistinguishable in B- and C-state thin filament configurations. We show here that tropomyosin can pivot about relatively fixed points on actin to accompany B-state/C-state structural transitions. We argue that at low Ca2+ concentrations C-terminal TnI domains attract tropomyosin, causing it to bend and then pivot toward the TnI, thus blocking myosin binding and contraction. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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