Cardiac troponin C (TnC) and a site I skeletal TnC mutant alter Ca<sup>2+</sup><i>versus</i> crossbridge contribution to force in rabbit skeletal fibres

Moreno-Gonzalez, Alicia; Fredlund, Jennifer; Regnier, Michael

doi:10.1113/jphysiol.2004.077891

Cited by 17 publications

(36 citation statements)

References 41 publications

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“…Under this two-state regulatory scheme, it was difficult to control Ca 2+ sensitivity in the force–pCa relationship, and we concluded that three states better represent the thin-filament regulatory system. This agrees with experiments suggesting that differences in skeletal and cardiac regulatory proteins are partially responsible for differences in cooperative force production between the two muscle types [28,72,73]. …”

Section: Methodssupporting

confidence: 91%

Sarcomere Lattice Geometry Influences Cooperative Myosin Binding in Muscle

2007

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In muscle, force emerges from myosin binding with actin (forming a cross-bridge). This actomyosin binding depends upon myofilament geometry, kinetics of thin-filament Ca2+ activation, and kinetics of cross-bridge cycling. Binding occurs within a compliant network of protein filaments where there is mechanical coupling between myosins along the thick-filament backbone and between actin monomers along the thin filament. Such mechanical coupling precludes using ordinary differential equation models when examining the effects of lattice geometry, kinetics, or compliance on force production. This study uses two stochastically driven, spatially explicit models to predict levels of cross-bridge binding, force, thin-filament Ca2+ activation, and ATP utilization. One model incorporates the 2-to-1 ratio of thin to thick filaments of vertebrate striated muscle (multi-filament model), while the other comprises only one thick and one thin filament (two-filament model). Simulations comparing these models show that the multi-filament predictions of force, fractional cross-bridge binding, and cross-bridge turnover are more consistent with published experimental values. Furthermore, the values predicted by the multi-filament model are greater than those values predicted by the two-filament model. These increases are larger than the relative increase of potential inter-filament interactions in the multi-filament model versus the two-filament model. This amplification of coordinated cross-bridge binding and cycling indicates a mechanism of cooperativity that depends on sarcomere lattice geometry, specifically the ratio and arrangement of myofilaments.

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Section: Methodssupporting

confidence: 91%

Sarcomere Lattice Geometry Influences Cooperative Myosin Binding in Muscle

2007

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“…However, in physiological conditions the steep cooperativity of thin filament activation is not dependent on myosin binding in the steady state (6,36,37). The present results extend this conclusion to the time domain; the dominant components of thin filament activation (phases 1 and 2) are much faster than myosin head binding, and are not affected by its presence (Figs.…”

Section: Discussionsupporting

confidence: 77%

Structural dynamics of troponin during activation of skeletal muscle

Fusi

Brunello

Sevrieva

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Time-resolved changes in the conformation of troponin in the thin filaments of skeletal muscle were followed during activation in situ by photolysis of caged calcium using bifunctional fluorescent probes in the regulatory and the coiled-coil (IT arm) domains of troponin. Three sequential steps in the activation mechanism were identified. The fastest step (1,100 s −1 ) matches the rate of Ca 2+ binding to the regulatory domain but also dominates the motion of the IT arm. The second step (120 s −1 ) coincides with the azimuthal motion of tropomyosin around the thin filament. The third step (15 s −1 ) was shown by three independent approaches to track myosin head binding to the thin filament, but is absent in the regulatory head. The results lead to a four-state structural kinetic model that describes the molecular mechanism of muscle activation in the thin filament-myosin head complex under physiological conditions. muscle regulation | excitation-contraction coupling | muscle signaling C ontraction of skeletal and cardiac muscle is initiated by a transient increase in the concentration of intracellular Ca 2+ ions, which bind to troponin in the thin filaments of the muscle sarcomere. This leads to azimuthal movement of tropomyosin around the thin filament, which uncovers the myosin binding sites on actin and allows the head domain of myosin from the thick filaments to bind to actin and generate force (1, 2). In vitro studies using isolated protein components showed that myosin head binding can produce a further motion of tropomyosin, at least in low [ATP] or rigor-like conditions (2-4), but the functional significance of this effect in physiological conditions and intact sarcomeres is not clear.To elucidate the molecular structural basis of muscle regulation and the role of myosin binding in situ, we introduced bifunctional fluorescent probes into the calcium-binding subunit of troponin, troponin C (TnC) (Fig. 1, yellow), in demembranated fibers from skeletal muscle (5-7). One probe cross-linked a pair of cysteines introduced into the C helix of TnC (Fig. 1, green), close to the regulatory Ca 2+ binding sites (Fig. 1, black spheres) in its N-terminal lobe, and reports the rotation and opening of this lobe on binding Ca 2+ (5). The N-lobe opening is associated with binding of the switch peptide of troponin I (TnI) (Fig. 1, blue) to a hydrophobic pocket on its surface, and this is a key step in the signaling pathway of calcium regulation (8, 9).A second probe was attached to the E helix of TnC (Fig. 1, magenta) in its C-terminal lobe, which contains a pair of divalent cation binding sites (Fig. 1, gray spheres) that can bind Mg 2+ as well as Ca 2+ . The C lobe of TnC is clasped between two long helices of TnI, one of which forms a coiled coil with part of the tropomyosin-binding component of troponin, troponin T (TnT) (Fig. 1, orange). The C lobe of TnC and these long TnI and TnT helices form a well-defined structural domain called the "IT arm" (9, 10). Although the C-lobe E helix of TnC is continuous with the N-lob...

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“…Under this two-state regulatory scheme, it was difficult to control Ca 2þ sensitivity in the force-pCa relationship, and we concluded that three states better represent the thin-filament regulatory system. This agrees with experiments suggesting that differences in skeletal and cardiac regulatory proteins are partially responsible for differences in cooperative force production between the two muscle types [28,72,73].…”

supporting

confidence: 91%

Sarcomere lattice geometry influences cooperative myosin binding in muscle

Tanner¹,

Daniel²,

Regnier³

2005

PLoS Comput Biol

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In muscle, force emerges from myosin binding with actin (forming a cross-bridge). This actomyosin binding depends upon myofilament geometry, kinetics of thin-filament Ca 2þ activation, and kinetics of cross-bridge cycling. Binding occurs within a compliant network of protein filaments where there is mechanical coupling between myosins along the thick-filament backbone and between actin monomers along the thin filament. Such mechanical coupling precludes using ordinary differential equation models when examining the effects of lattice geometry, kinetics, or compliance on force production. This study uses two stochastically driven, spatially explicit models to predict levels of cross-bridge binding, force, thin-filament Ca 2þ activation, and ATP utilization. One model incorporates the 2-to-1 ratio of thin to thick filaments of vertebrate striated muscle (multi-filament model), while the other comprises only one thick and one thin filament (two-filament model). Simulations comparing these models show that the multi-filament predictions of force, fractional cross-bridge binding, and cross-bridge turnover are more consistent with published experimental values. Furthermore, the values predicted by the multi-filament model are greater than those values predicted by the two-filament model. These increases are larger than the relative increase of potential inter-filament interactions in the multi-filament model versus the two-filament model. This amplification of coordinated cross-bridge binding and cycling indicates a mechanism of cooperativity that depends on sarcomere lattice geometry, specifically the ratio and arrangement of myofilaments.

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Cardiac troponin C (TnC) and a site I skeletal TnC mutant alter Ca²⁺versus crossbridge contribution to force in rabbit skeletal fibres

Cited by 17 publications

References 41 publications

Sarcomere Lattice Geometry Influences Cooperative Myosin Binding in Muscle

Sarcomere Lattice Geometry Influences Cooperative Myosin Binding in Muscle

Structural dynamics of troponin during activation of skeletal muscle

Sarcomere lattice geometry influences cooperative myosin binding in muscle

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Cardiac troponin C (TnC) and a site I skeletal TnC mutant alter Ca2+versus crossbridge contribution to force in rabbit skeletal fibres

Cited by 17 publications

References 41 publications

Sarcomere Lattice Geometry Influences Cooperative Myosin Binding in Muscle

Sarcomere Lattice Geometry Influences Cooperative Myosin Binding in Muscle

Structural dynamics of troponin during activation of skeletal muscle

Sarcomere lattice geometry influences cooperative myosin binding in muscle

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Cardiac troponin C (TnC) and a site I skeletal TnC mutant alter Ca²⁺versus crossbridge contribution to force in rabbit skeletal fibres