Structural Model of Weak Binding Actomyosin in the Prepowerstroke State

Várkuti, Boglárka H.; Yang, Zhenhui; Málnási‐Csizmadia, András

doi:10.1074/jbc.m114.606665

Cited by 11 publications

(11 citation statements)

References 37 publications

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“…The activation loop (I1634-G1640) preceding the HLH motif has been suggested to activate myosins through contacts with actin’s negatively charged N terminus (Varkuti et al, 2012; Varkuti et al, 2015). Indeed, K1637 forms a possible salt bridge with subunit i + 2 residue 4E, partially stabilizing actin’s flexible N terminus (Figure S4C).…”

Section: Resultsmentioning

confidence: 99%

Structural basis for tunable control of actin dynamics by myosin-15 in mechanosensory stereocilia

Gong

Jiang

Moreland

et al. 2021

Preprint

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SummaryThe motor protein myosin-15 is necessary for the development and maintenance of mechanosensory stereocilia, and myosin-15 mutations cause profound deafness. In a companion study, we report that myosin-15 nucleates actin filament (“F-actin”) assembly and identify a progressive hearing loss mutation (p.D1647G, “jordan”) which disrupts stereocilia elongation by inhibiting actin polymerization. Here, we present cryo-EM structures of myosin-15 bound to F-actin, providing a framework for interpreting deafness mutations and their impacts on myosin-stimulated actin assembly. Rigor myosin-15 evokes conformational changes in F-actin yet maintains flexibility in actin’s D-loop, which mediates inter-subunit contacts, while the jordan mutant locks the D-loop in a single conformation. ADP-bound myosin-15 also locks the D-loop, which correspondingly blunts actin-polymerization stimulation. We propose myosin-15 enhances polymerization by bridging actin protomers, regulating nucleation efficiency by modulating actin’s structural plasticity in a myosin nucleotide-state dependent manner. This tunable regulation of actin polymerization could be harnessed to precisely control stereocilium height.

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Section: Resultsmentioning

confidence: 99%

Structural basis for tunable control of actin dynamics by myosin-15 in mechanosensory stereocilia

Gong

Jiang

Moreland

et al. 2021

Preprint

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“…It has been revealed by experiments involving actin and a myosin head (myosin subfragment S1) that the enthalpic and entropic components of the binding free energy are both positive, irrespective of the presence of a nucleotide (4,5), which implies that the binding is entropically driven. By contrast, several results from molecular dynamics (MD) simulations have suggested that the binding is energetically driven (6)(7)(8). Lorenz and Holmes have obtained an atomic structural model of rigor (strong)-binding actomyosin using an MD simulation based on an electron microscopy map of the actomyosin complex and the crystal structures of actin and myosin monomers (6).…”

Section: Introductionmentioning

confidence: 99%

“…Okazaki et al performed in silico titration by employing a coarse-grained actomyosin model with the Debye-Hu ¨ckel solvent model (7) and claimed that the binding is driven by actin-myosin electrostatic attractive interaction. Va ´rkuti et al calculated the binding free energy using the molecular mechanics Poisson-Boltzmann surface area method (8). Their results also indicate that salt bridges and hydrogen bonds between actin and myosin play important roles in the binding.…”

Section: Introductionmentioning

confidence: 99%

Statistical Thermodynamics for Actin-Myosin Binding: The Crucial Importance of Hydration Effects

Oshima

Hayashi

Kinoshita

2016

Biophysical Journal

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Actomyosin is an important molecular motor, and the binding of actin and myosin is an essential research target in biophysics. Nevertheless, the physical factors driving or opposing the binding are still unclear. Here, we investigate the role of water in actin-myosin binding using the most reliable statistical-mechanical method currently available for assessing biomolecules immersed in water. This method is characterized as follows: water is treated not as a dielectric continuum but as an ensemble of molecules; the polyatomic structures of proteins are taken into consideration; and the binding free energy is decomposed into physically insightful entropic and energetic components by accounting for the hydration effect to its full extent. We find that the actin-myosin binding brings large gains of electrostatic and Lennard-Jones attractive interactions. However, these gains are accompanied by even larger losses of actin-water and myosin-water electrostatic and LJ attractive interactions. Although roughly half of the energy increase due to the losses is cancelled out by the energy decrease arising from structural reorganization of the water released upon binding, the remaining energy increase is still larger than the energy decrease brought by the gains mentioned above. Hence, the net change in system energy is positive, which opposes binding. Importantly, the binding is driven by a large gain of configurational entropy of water, which surpasses the positive change in system energy and the conformational entropy loss occurring for actin and myosin. The principal physical origin of the large water-entropy gain is as follows: the actin-myosin interface is closely packed with the achievement of high shape complementarity on the atomic level, leading to a large increase in the total volume available to the translational displacement of water molecules in the system and a resultant reduction of water crowding (i.e., entropic correlations among water molecules).

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“…Arg232 has been discussed earlier to play a critical role for myosin function through a complex salt-bridge found in a scallop myosin crystal structure [ 44 ], and this is consistent with studies suggesting particular arginine residues to serve as key connectors between functional subunits in proteins [ 50 ]. In conclusion, our structural and computational study sheds light on a new myosin conformation and the two-step mechanism of the force-generating myosin power stroke, providing molecular insights into the potential conformational transitions associated with ADP release, thereby contributing to recent progress [ 24 , 25 , 26 , 31 , 51 ] in resolving the mechanism of force production and cellular motility by molecular motors.…”

Section: Discussionmentioning

confidence: 85%

“…The power stroke is initiated by ATP hydrolysis, followed by reattachment of the myosin motor in the pre-power stroke state to its actin filament track, coupled to conformational changes that finally lead to the release of the hydrolysis products and to force generation. The exact sequence of events is critically discussed in the field, and several models have been proposed for the conformational states involved in the power stroke [ 24 , 25 , 26 , 27 ]. The conformational changes required for force production are assumed to be driven by actin reattachment and the sequential release of inorganic phosphate (P i ), Mg 2+ , and adenosine diphosphate (ADP).…”

Section: Introductionmentioning

confidence: 99%

Structural and Computational Insights into a Blebbistatin-Bound Myosin•ADP Complex with Characteristics of an ADP-Release Conformation along the Two-Step Myosin Power Stoke

Ewert

Franz

Tsiavaliaris

et al. 2020

IJMS

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The motor protein myosin drives a wide range of cellular and muscular functions by generating directed movement and force, fueled through adenosine triphosphate (ATP) hydrolysis. Release of the hydrolysis product adenosine diphosphate (ADP) is a fundamental and regulatory process during force production. However, details about the molecular mechanism accompanying ADP release are scarce due to the lack of representative structures. Here we solved a novel blebbistatin-bound myosin conformation with critical structural elements in positions between the myosin pre-power stroke and rigor states. ADP in this structure is repositioned towards the surface by the phosphate-sensing P-loop, and stabilized in a partially unbound conformation via a salt-bridge between Arg131 and Glu187. A 5 Å rotation separates the mechanical converter in this conformation from the rigor position. The crystallized myosin structure thus resembles a conformation towards the end of the two-step power stroke, associated with ADP release. Computationally reconstructing ADP release from myosin by means of molecular dynamics simulations further supported the existence of an equivalent conformation along the power stroke that shows the same major characteristics in the myosin motor domain as the resolved blebbistatin-bound myosin-II·ADP crystal structure, and identified a communication hub centered on Arg232 that mediates chemomechanical energy transduction.

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Structural Model of Weak Binding Actomyosin in the Prepowerstroke State

Cited by 11 publications

References 37 publications

Structural basis for tunable control of actin dynamics by myosin-15 in mechanosensory stereocilia

Structural basis for tunable control of actin dynamics by myosin-15 in mechanosensory stereocilia

Statistical Thermodynamics for Actin-Myosin Binding: The Crucial Importance of Hydration Effects

Structural and Computational Insights into a Blebbistatin-Bound Myosin•ADP Complex with Characteristics of an ADP-Release Conformation along the Two-Step Myosin Power Stoke

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