Myosin Structure, Allostery, and Mechano-Chemistry

Preller, Matthias; Manstein, Dietmar J.

doi:10.1016/j.str.2013.09.015

Cited by 61 publications

(85 citation statements)

References 125 publications

(138 reference statements)

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“…Residue D588 is positioned behind a loop (residues 567-576), which has been computationally implicated and validated in actin binding [28][29][30] ( Figure III in the Data Supplement). We propose that D588 makes specific interactions with this loop, contributing to its conformational stability.…”

Section: D588amentioning

confidence: 99%

Recessive MYH6 Mutations in Hypoplastic Left Heart With Reduced Ejection Fraction

Theis

Zimmermann

Evans

et al. 2015

Circ Cardiovasc Genet

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Here, we used whole genome sequencing (WGS) in HLH probands and phenotypically characterized family members to overcome existing barriers to HLH gene discovery. ThisBackground-The molecular underpinnings of hypoplastic left heart are poorly understood. Staged surgical palliation has dramatically improved survival, yet eventual failure of the systemic right ventricle necessitates cardiac transplantation in a subset of patients. We sought to identify genetic determinants of hypoplastic left heart with latent right ventricular dysfunction in individuals with a Fontan circulation. Methods and Results-Evaluation of cardiac structure and function by echocardiography in patients with hypoplastic left heart and their first-degree relatives identified 5 individuals with right ventricular ejection fraction ≤40% after Fontan operation. Whole genome sequencing was performed on DNA from 21 family members, filtering for genetic variants with allele frequency <1% predicted to alter protein structure or expression. Secondary family-based filtering for de novo and recessive variants revealed rare inherited missense mutations on both paternal and maternal alleles of MYH6, encoding myosin heavy chain 6, in 2 patients who developed right ventricular dysfunction 3 to 11 years postoperatively. Parents and siblings who were heterozygous carriers had normal echocardiograms. Protein modeling of the 4 highly conserved amino acid substitutions, residing in both head and tail domains, predicted perturbation of protein structure and function. Conclusions-In contrast to dominant MYH6 mutations with variable penetrance identified in other congenital heart defects and dilated cardiomyopathy, this study reveals compound heterozygosity for recessive MYH6 mutations in patients with hypoplastic left heart and reduced systemic right ventricular ejection fraction. These findings implicate a shared molecular basis for the developmental arrest and latent myopathy of left and right ventricles, respectively. (Circ Cardiovasc Genet. 2015;8:564-571.

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Section: D588amentioning

confidence: 99%

Recessive MYH6 Mutations in Hypoplastic Left Heart With Reduced Ejection Fraction

Theis

Zimmermann

Evans

et al. 2015

Circ Cardiovasc Genet

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“…Bundled within an intricate and highly regulated myofibril lattice, muscle myosin II converts the chemical energy released by ATP binding and hydrolysis into mechanical work, executing a series of structural transitions that generate force on actin and shorten each muscle cell (1,2). Coupling of actin binding, nucleotide hydrolysis, and lever arm movement within myosin's catalytic domain (CD) is essential for proper function of the contractile apparatus (3,4).…”

mentioning

confidence: 99%

High-resolution helix orientation in actin-bound myosin determined with a bifunctional spin label

Binder

Cornea

Thompson

et al. 2015

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

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Using electron paramagnetic resonance (EPR) of a bifunctional spin label (BSL) bound stereospecifically to Dictyostelium myosin II, we determined with high resolution the orientation of individual structural elements in the catalytic domain while myosin is in complex with actin. BSL was attached to a pair of engineered cysteine side chains four residues apart on known α-helical segments, within a construct of the myosin catalytic domain that lacks other reactive cysteines. EPR spectra of BSL-myosin bound to actin in oriented muscle fibers showed sharp three-line spectra, indicating a well-defined orientation relative to the actin filament axis. Spectral analysis indicated that orientation of the spin label can be determined within <2.1°accuracy, and comparison with existing structural data in the absence of nucleotide indicates that helix orientation can also be determined with <4.2°accuracy. We used this approach to examine the crucial ADP release step in myosin's catalytic cycle and detected reversible rotations of two helices in actin-bound myosin in response to ADP binding and dissociation. One of these rotations has not been observed in myosin-only crystal structures.T he myosin family of molecular motors is responsible for numerous vital functions in eukaryotes, including the contraction of striated muscle. Bundled within an intricate and highly regulated myofibril lattice, muscle myosin II converts the chemical energy released by ATP binding and hydrolysis into mechanical work, executing a series of structural transitions that generate force on actin and shorten each muscle cell (1, 2). Coupling of actin binding, nucleotide hydrolysis, and lever arm movement within myosin's catalytic domain (CD) is essential for proper function of the contractile apparatus (3, 4).Myosin function requires actin, and thus an understanding of its mechanism requires analysis of both proteins in complex. However, no crystals of actin-myosin complexes have been reported, so the resolution of actin-bound myosin structures is currently limited to that of electron microscopy. Furthermore, X-ray crystallography and electron microscopy produce only static structures in frozen or crystalline environments, which cannot accurately render the dynamics, disorder, and structural transitions that are essential to understanding function and pathology (4, 5).In contrast, site-directed spectroscopy can be used to examine the actin-myosin complex under more physiological conditions. Both fluorescence and electron paramagnetic resonance (EPR) have been used in complement to examine the structural dynamics of myosin bound to actin (6, 7). EPR offers superior orientational resolution, due to the high sensitivity of the EPR spectrum to alignment of a spin label in the applied magnetic field. A wellplaced spin label can provide direct information about orientation and dynamics in the vicinity of the labeling site, a strategy that has proven powerful in the study of myosin in oriented muscle fibers (7-9). However, conventional methods for site-direc...

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“…Myosin motors, like all cytoskeletal motors, couple the hydrolysis of ATP to a reversible conformational change in their motor domain, which is then translated into a larger movement by the stiff neck region at the C-terminal end of the motor domain (Preller and Manstein, 2013). This hydrolytic cycle is coordinated with the binding and release of an actin filament such that the motor protein takes one step toward the plus end of the filament with every ATP molecule used.…”

Section: Not All Motors Are Created Equal: Differences In Enzymatic Pmentioning

confidence: 99%

Update on Myosin Motors: Molecular Mechanisms and Physiological Functions

Ryan

Nebenführ

2017

Plant Physiol.

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Myosin Structure, Allostery, and Mechano-Chemistry

Cited by 61 publications

References 125 publications

Recessive MYH6 Mutations in Hypoplastic Left Heart With Reduced Ejection Fraction

Recessive MYH6 Mutations in Hypoplastic Left Heart With Reduced Ejection Fraction

High-resolution helix orientation in actin-bound myosin determined with a bifunctional spin label

Update on Myosin Motors: Molecular Mechanisms and Physiological Functions

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