Mavacamten stabilizes a folded-back sequestered super-relaxed state of β-cardiac myosin

Anderson, Robert L.; Trivedi, Darshan V.; Sarkar, Saswata S.; Henze, Marcus; Ma, Weikang; Gong, Henry; Rogers, Christopher S.; Wong, Fiona; Morck, Makenna M.; Seidman, Jonathan G.; Ruppel, Kathleen M.; Irving, Thomas C.; Cooke, Roger; Green, Eric M.; Spudich, James A.

doi:10.1101/266783

Cited by 12 publications

(13 citation statements)

References 60 publications

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“…The small molecule drug candidate mavacamten has been found to decrease contractility and suppress the development of hypertrophy and fibrosis in HCM mouse models [ 83 ]. Mavacamten appears to reduce the basal release rates of ADP and Pi [ 84 ], by stabilizing the myosin heads in an SRX state [ 23 ], similarly to blebbistatin. In support of this notion, we have shown that mavacampten significantly increases the myosin layer line intensities in relaxed skinned porcine cardiac muscle [ 23 ], consistent with an enrichment of the quasi-helically ordered SRX state.…”

Section: Discussionmentioning

confidence: 99%

“…The SRX state has been characterized as a state where myosin has a much lower ATPase rate than under normal conditions [ 20 ], explaining the low energy consumption in resting muscle. Structurally, myosin heads in the SRX state have been proposed to adopt the so-called interacting-head motif (IHM) where one of the two heads of a myosin molecule is folded back on to its own coiled-coil S2 tail [ 21 , 22 , 23 ]. In contrast, in the DRX state, myosin heads are presumed to be disordered and freely moving in the myofilament lattice with ATPase activity as high as with isolated myosin [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

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Myosin Head Configurations in Resting and Contracting Murine Skeletal Muscle

Gong

Irving

2018

IJMS

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Transgenic mouse models have been important tools for studying the relationship of genotype to phenotype for human diseases, including those of skeletal muscle. We show that mouse skeletal muscle can produce high quality X-ray diffraction patterns establishing the mouse intact skeletal muscle X-ray preparation as a potentially powerful tool to test structural hypotheses in health and disease. A notable feature of the mouse model system is the presence of residual myosin layer line intensities in contracting mouse muscle patterns. This provides an additional tool, along with the I1,1/I1,0 intensity ratio, for estimating the proportions of active versus relaxed myosin heads under a given set of conditions that can be used to characterize a given physiological condition or mutant muscle type. We also show that analysis of the myosin layer line intensity distribution, including derivation of the myosin head radius, Rm, may be used to study the role of the super-relaxed state in myosin regulation. When the myosin inhibitor blebbistatin is used to inhibit force production, there is a shift towards a highly quasi-helically ordered configuration that is distinct from the normal resting state, indicating there are more than one helically ordered configuration for resting crossbridges.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Myosin Head Configurations in Resting and Contracting Murine Skeletal Muscle

Gong

Irving

2018

IJMS

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“…While beyond the scope of this study, the assumption that the step size is unaffected could be tested using a single-molecule laser trap assay. Also, detailed direct biophysical measurements of the load dependence of the strongly-bound state are possible using Harmonic Force Spectroscopy (46) as well as measurements of the extent of sequestering of heads into a superrelaxed state (47). Furthermore, significant differences may be found using regulated thin filaments rather than purified actin in the ATPase measurements (14).…”

Section: Discussionmentioning

confidence: 99%

Myosin motor domains carrying mutations implicated in early or late onset hypertrophic cardiomyopathy have similar properties

Vera

Johnson

Walklate

et al. 2019

Journal of Biological Chemistry

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Hypertrophic cardiomyopathy (HCM) is a common genetic disorder characterized by left ventricular hypertrophy and cardiac hyper-contractility. Mutations in the β-cardiac myosin heavy chain gene (β-MyHC) are a major cause of HCM, but the specific mechanistic changes to myosin function that lead to this disease remain incompletely understood. Predicting the severity of any β-MyHC mutation is hindered by a lack of detailed examinations at the molecular level. Moreover, because HCM can take ≥20 years to develop, the severity of the mutations must be somewhat subtle. We hypothesized that mutations that result in early onset disease would have more severe changes in function than do later onset mutations. Here, we performed steady-state and transient kinetic analyses of myosins carrying one of seven missense mutations in the motor domain. Of these seven, four were previously identified in early onset cardiomyopathy screens. We used the parameters derived from these analyses to model the ATP-driven cross-bridge cycle. Contrary to our hypothesis, the results indicated no clear differences between early and late onset HCM mutations. Despite the lack of distinction between early and late onset HCM, the predicted occupancy of the force-holding actin·myosin·ADP complex at [Actin] = 3 Kapp along with the closely related duty ratio (the fraction of myosin in strongly attached force-holding states), and the measured ATPases all changed in parallel (in both sign and degree of change) compared with wildtype (WT) values. Six of the seven HCM mutations were clearly distinct from a set of previously characterized DCM mutations.

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“…At present, the IHM and the super-relaxed state have only been directly connected for the R403Q myosin mutation [ 112 ], but the weight of indirect evidence is compelling. The correlation of mutations with potential to destabilise the IHM seems solid for myosin heavy chain mutations and also for myosin light chain mutations and MyBP-C mutations causing haploinsufficiency.…”

Section: Unifying Hypothesis For Myosin and Mybp-c Mutations Causimentioning

confidence: 99%

“…It has been shown to be effective both in vitro and in vivo in reversing most of the basic symptoms of HCM [ 113 , 114 ]. A recent study has shown that the mode of action of Mavacampten is to stabilise the IHM structure and enhance the super-relaxed state of myosin [ 112 ].…”

Section: Unifying Hypothesis For Myosin and Mybp-c Mutations Causimentioning

confidence: 99%

The Molecular Mechanisms of Mutations in Actin and Myosin that Cause Inherited Myopathy

Marston

2018

IJMS

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The discovery that mutations in myosin and actin genes, together with mutations in the other components of the muscle sarcomere, are responsible for a range of inherited muscle diseases (myopathies) has revolutionized the study of muscle, converting it from a subject of basic science to a relevant subject for clinical study and has been responsible for a great increase of interest in muscle studies. Myopathies are linked to mutations in five of the myosin heavy chain genes, three of the myosin light chain genes, and three of the actin genes. This review aims to determine to what extent we can explain disease phenotype from the mutant genotype. To optimise our chances of finding the right mechanism we must study a myopathy where there are a large number of different mutations that cause a common phenotype and so are likely to have a common mechanism: a corollary to this criterion is that if any mutation causes the disease phenotype but does not correspond to the proposed mechanism, then the whole mechanism is suspect. Using these criteria, we consider two cases where plausible genotype-phenotype mechanisms have been proposed: the actin “A-triad” and the myosin “mesa/IHD” models.

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Mavacamten stabilizes a folded-back sequestered super-relaxed state of β-cardiac myosin

Cited by 12 publications

References 60 publications

Myosin Head Configurations in Resting and Contracting Murine Skeletal Muscle

Myosin Head Configurations in Resting and Contracting Murine Skeletal Muscle

Myosin motor domains carrying mutations implicated in early or late onset hypertrophic cardiomyopathy have similar properties

The Molecular Mechanisms of Mutations in Actin and Myosin that Cause Inherited Myopathy

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