The “Roll and Lock” Mechanism of Force Generation in Muscle

Ferenczi, Michael A.; Bershitsky, Sergey Y.; Koubassova, Natalia A.; Siththanandan, Verl; Helsby, W.; Panine, Pierre; Roessle, Manfred; Narayanan, Theyencheri; Tsaturyan, Andrey K.

doi:10.1016/j.str.2004.11.007

Cited by 65 publications

(109 citation statements)

References 47 publications

(6 reference statements)

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“…In particular, because cross-bridges strain at P 0 is Ϸ2 nm (20), our data show that a significant fraction of cross-bridge compliance may be located in the bond. Such a compliance is consistent with data in literature suggesting that part of working stroke might be caused by a rotation of the motor domain about its contact with actin (34)(35)(36).…”

Section: Discussionsupporting

confidence: 92%

Characterization of actomyosin bond properties in intact skeletal muscle by force spectroscopy

Colombini

Bagni

Romano

et al. 2007

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

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Force generation and motion in skeletal muscle result from interaction between actin and myosin myofilaments through the cyclical formation and rupture of the actomyosin bonds, the crossbridges, in the overlap region of the sarcomeres. Actomyosin bond properties were investigated here in single intact muscle fibers by using dynamic force spectroscopy. The force needed to forcibly detach the cross-bridge ensemble in the half-sarcomere (hs) was measured in a range of stretching velocity between 3.4 ؋ 10 3 nm⅐hs ؊1 ⅐s ؊1 or 3.3 fiber length per second (l0s ؊1 ) and 6. cross-bridges ͉ rupture force ͉ detachment rate constant ͉ fast stretches A tomic force microscopy (1-4) and force spectroscopy (5, 6) have been used to reveal the properties of the weak noncovalent bond between receptor molecules and their ligands, and in particular dynamic force spectroscopy has been used to define in detail the properties of the single biotin-avidin bond (1-3, 7). As regarding molecular motors, the optical tweezers technique has allowed the investigation of the properties of an individual actomyosin bond and to measure the force and unitary step displacement generated (8-10). The properties of the single actomyosin bond under rigor conditions were also investigated by measuring the dependence of the bond lifetime on the applied load (11). It was found that bond lifetime was strongly reduced when a load was applied to the bond, in good quantitative agreement with the prediction of Bell theory (12). These results on single actomyosin interaction represent a great step forward in our understanding of molecular mechanism of force generation in muscle; however, they were generally obtained under experimental conditions that differ from those encountered by the same motors in native preparation. In living skeletal muscle, myosin heads (the molecular motors) are distributed over the myosin filament in a very regular fashion, and both actin and myosin filaments are arranged in a quasicrystalline lattice that maintains a precise geometrical relationship between myosin heads (or fraction S1 of myosin molecule) and the active sites regularly distributed along the actin filament (13). This remarkable order is lost when experiments are made on single molecules, and this may affect the bond properties and force developed. In addition, at physiological ionic strength, actin filaments tend to detach from myosin heads, and it is therefore necessary to perform the above experiments at low ionic strength. However, it is known that molecular motor performance strongly depends on ionic strength (14). The force generated is also strongly affected by myosin S1 orientation, which is not easily controlled in single-molecule experiments (14). This means that the force measured by the recording apparatus, usually along the actin filament axis, may not represent accurately the real capability of the motors when working in a regularly ordered array. The same is true in experiments in which an external load is applied to the single bond, because it is usually d...

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Section: Discussionsupporting

confidence: 92%

Characterization of actomyosin bond properties in intact skeletal muscle by force spectroscopy

Colombini

Bagni

Romano

et al. 2007

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

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“…Moreover, in our model the E163 and E164 residues may interact with Arg and Lys residues of a myosin head weakly bound to actin close to the Tm pseudo-repeat 5. The weak-to-strong transition of the head, which is accompanied by its axial and azimuthal tilt with respect to the actin filament, plays an important role in myosin motor function [34,35]. In conclusion, the results presented here shed light on the functional importance of such extraordinary structural features of Tm as the presence of non-canonical residues Asp137 and Gly126 in the middle part of the molecule.…”

Section: +mentioning

confidence: 55%

Structural and functional effects of two stabilizing substitutions, D137L and G126R, in the middle part of α‐tropomyosin molecule

et al. 2014

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Tropomyosin (Tm) is an a-helical coiled-coil protein that binds along the length of actin filament and plays an essential role in the regulation of muscle contraction. There are two highly conserved non-canonical residues in the middle part of the Tm molecule, Asp137 and Gly126, which are thought to impart conformational instability (flexibility) to this region of Tm which is considered crucial for its regulatory functions. It was shown previously that replacement of these residues by canonical ones (Leu substitution for Asp137 and Arg substitution for Gly126) results in stabilization of the coiled-coil in the middle of Tm and affects its regulatory function. Here we employed various methods to compare structural and functional features of Tm mutants carrying stabilizing substitutions Arg137Leu and Gly126Arg. Moreover, we for the first time analyzed the properties of Tm carrying both these substitutions within the same molecule. The results show that both substitutions similarly stabilize the Tm coiled-coil structure, and their combined action leads to further significant stabilization of the Tm molecule. This stabilization not only enhances maximal sliding velocity of regulated actin filaments in the in vitro motility assay at high Ca 2+ concentrations but also increases Ca 2+ sensitivity of the actin-myosin interaction underlying this sliding. We propose that the effects of these substitutions on the Ca 2+ -regulated actin-myosin interaction can be accounted for not only by decreased flexibility of actin-bound Tm but also by their influence on the interactions between the middle part of Tm and certain sites of the myosin head.

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“…The rate of actin binding is formulated from the 'swing-roll-lock' mechanism postulated on the basis of a recent X-ray diffraction study. 19 Transition rates for a working stroke can be rigorously derived from Kramers' theory, using a flat energy landscape for the detached head. 70 Large strains will dissociate the actomoyosin bond, 44,55 and kinetic and mechanical mechanisms are formulated.…”

Section: Introductionmentioning

confidence: 99%

Towards a Unified Theory of Muscle Contraction. I: Foundations

et al. 2008

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Molecular models of contractility in striated muscle require an integrated description of the action of myosin motors, firstly in the filament lattice of the half-sarcomere. Existing models do not adequately reflect the biochemistry of the myosin motor and its sarcomeric environment. The biochemical actin-myosin-ATP cycle is reviewed, and we propose a model cycle with two 4- to 5-nm working strokes, where phosphate is released slowly after the first stroke. A smaller third stroke is associated with ATP-induced detachment from actin. A comprehensive model is defined by applying such a cycle to all myosin-S1 heads in the half-sarcomere, subject to generic constraints as follows: (a) all strain-dependent kinetics required for actin-myosin interactions are derived from reaction-energy landscapes and applied to dimeric myosin, (b) actin-myosin interactions in the half-sarcomere are controlled by matching rules derived from the structure of the filaments, so that each dimer may be associated with a target zone of three actin sites, and (c) the myosin and actin filaments are treated as elastically extensible. Numerical predictions for such a model are presented in the following paper.

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The “Roll and Lock” Mechanism of Force Generation in Muscle

Cited by 65 publications

References 47 publications

Characterization of actomyosin bond properties in intact skeletal muscle by force spectroscopy

Characterization of actomyosin bond properties in intact skeletal muscle by force spectroscopy

Structural and functional effects of two stabilizing substitutions, D137L and G126R, in the middle part of α‐tropomyosin molecule

Towards a Unified Theory of Muscle Contraction. I: Foundations

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