Direct detection of the myosin super-relaxed state and interacting-heads motif in solution

Chu, Sami; Muretta, Joseph M.; Thomas, David D.

doi:10.1016/j.jbc.2021.101157

Cited by 41 publications

(47 citation statements)

References 23 publications

(47 reference statements)

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“…The opposite of what might be expected if the thick filament stabilizes the SRX form of myosin. In a recent paper, Chu et al (2021) ( 20 ) also reported a mismatch between estimates of the fraction of myosin heads in the SRX state and the IHM.…”

Section: Discussionmentioning

confidence: 99%

“…Work on isolated skinned muscle fibers, myofibrils, myosin thick filaments, heavy meromyosin (HMM), and myosin has revealed the presence of two populations of “relaxed” myosin heads ( 16 , 18 , 19 , 20 ). Those with the typical ATPase turnover rate of a single isolated motor domain (0.05 s-1), and a second population with a much slower turnover rate (∼0.005 s-1) the SRX population.…”

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confidence: 99%

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Exploring the super-relaxed state of myosin in myofibrils from fast-twitch, slow-twitch, and cardiac muscle

Walklate

Kao

Regnier

et al. 2022

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Exploring the super-relaxed state of myosin in myofibrils from fast-twitch, slow-twitch, and cardiac muscle

Walklate

Kao

Regnier

et al. 2022

Journal of Biological Chemistry

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“…They hypothesized that myosin heads can occupy an SRX without adopting a folded IHM conformation that is further stabilized by intramolecular interactions similar to those existing in the IHM ( 20 ). Additional support comes from time-resolved fluorescence resonance energy transfer experiments showing that the SRX can exist in the absence of a conventional IHM, suggesting that the IHM is sufficient but not necessary to produce the SRX kinetic state ( 41 ). The molecular pathogenesis of DCM was recently assessed in the context of the myosin SRX state and IHM paradigm ( 24 ).…”

Section: Discussionmentioning

confidence: 99%

Molecular basis of force-pCa relation in MYL2 cardiomyopathy mice: Role of the super-relaxed state of myosin

Yuan

Kazmierczak

Liang

et al. 2022

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

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In this study, we investigated the role of the super-relaxed (SRX) state of myosin in the structure–function relationship of sarcomeres in the hearts of mouse models of cardiomyopathy-bearing mutations in the human ventricular regulatory light chain (RLC, MYL2 gene). Skinned papillary muscles from hypertrophic (HCM–D166V) and dilated (DCM–D94A) cardiomyopathy models were subjected to small-angle X-ray diffraction simultaneously with isometric force measurements to obtain the interfilament lattice spacing and equatorial intensity ratios (I11/I10) together with the force-pCa relationship over a full range of [Ca2+] and at a sarcomere length of 2.1 μm. In parallel, we studied the effect of mutations on the ATP-dependent myosin energetic states. Compared with wild-type (WT) and DCM–D94A mice, HCM–D166V significantly increased the Ca2+ sensitivity of force and left shifted the I11/I10-pCa relationship, indicating an apparent movement of HCM–D166V cross-bridges closer to actin-containing thin filaments, thereby allowing for their premature Ca2+ activation. The HCM–D166V model also disrupted the SRX state and promoted an SRX-to-DRX (super-relaxed to disordered relaxed) transition that correlated with an HCM-linked phenotype of hypercontractility. While this dysregulation of SRX ↔ DRX equilibrium was consistent with repositioning of myosin motors closer to the thin filaments and with increased force-pCa dependence for HCM–D166V, the DCM–D94A model favored the energy-conserving SRX state, but the structure/function–pCa data were similar to WT. Our results suggest that the mutation-induced redistribution of myosin energetic states is one of the key mechanisms contributing to the development of complex clinical phenotypes associated with human HCM–D166V and DCM–D94A mutations.

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“…However, the myosin motors are not immediately available for interaction with actin, as they are folded into helical tracks on the surface of the thick filament in an asymmetric conformation called the “interacting heads motif” ( Zoghbi et al, 2008 ; AL-Khayat et al, 2013 ), which was first identified in smooth muscle myosin ( Wendt et al, 2001 ) and in isolated thick filaments from skeletal muscle of the tarantula ( Woodhead et al, 2005 ). This folded conformation is assumed to inhibit actomyosin interaction and myosin adenosine triphosphatase, locking the myosin motors in an energy-saving state that has been identified with the “super-relaxed state” observed biochemically ( Stewart et al, 2010 ; Hooijman et al, 2011 ), although other factors may also modulate that state ( Chu et al, 2021 ). Recent studies on cardiac muscle using x-ray diffraction ( Reconditi et al, 2017 ; Brunello et al, 2020 ) and fluorescent probes on myosin ( Park-Holohan et al, 2021 ) showed that in the resting phase of the cardiac cycle between beats, called “diastole,” the myosin motors are folded onto the thick filament surface in a conformation consistent with the interacting heads motif.…”

Section: Introductionmentioning

confidence: 99%

Cooling intact and demembranated trabeculae from rat heart releases myosin motors from their inhibited conformation

Ovejero

Fusi

Park-Holohan

et al. 2022

Journal of General Physiology

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Myosin filament–based regulation supplements actin filament–based regulation to control the strength and speed of contraction in heart muscle. In diastole, myosin motors form a folded helical array that inhibits actin interaction; during contraction, they are released from that array. A similar structural transition has been observed in mammalian skeletal muscle, in which cooling below physiological temperature has been shown to reproduce some of the structural features of the activation of myosin filaments during active contraction. Here, we used small-angle x-ray diffraction to characterize the structural changes in the myosin filaments associated with cooling of resting and relaxed trabeculae from the right ventricle of rat hearts from 39°C to 7°C. In intact quiescent trabeculae, cooling disrupted the folded helical conformation of the myosin motors and induced extension of the filament backbone, as observed in the transition from diastole to peak systolic force at 27°C. Demembranation of trabeculae in relaxing conditions induced expansion of the filament lattice, but the structure of the myosin filaments was mostly preserved at 39°C. Cooling of relaxed demembranated trabeculae induced changes in motor conformation and filament structure similar to those observed in intact quiescent trabeculae. Osmotic compression of the filament lattice to restore its spacing to that of intact trabeculae at 39°C stabilized the helical folded state against disruption by cooling. The myosin filament structure and motor conformation of intact trabeculae at 39°C were largely preserved in demembranated trabeculae at 27°C or above in the presence of Dextran, allowing the physiological mechanisms of myosin filament–based regulation to be studied in those conditions.

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Direct detection of the myosin super-relaxed state and interacting-heads motif in solution

Cited by 41 publications

References 23 publications

Exploring the super-relaxed state of myosin in myofibrils from fast-twitch, slow-twitch, and cardiac muscle

Exploring the super-relaxed state of myosin in myofibrils from fast-twitch, slow-twitch, and cardiac muscle

Molecular basis of force-pCa relation in MYL2 cardiomyopathy mice: Role of the super-relaxed state of myosin

Cooling intact and demembranated trabeculae from rat heart releases myosin motors from their inhibited conformation

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