Muscle contraction: Sliding filament history, sarcomere dynamics and the two Huxleys

Squire, John M.

doi:10.21542/gcsp.2016.11

Cited by 30 publications

(27 citation statements)

References 63 publications

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“…During muscle contraction, actin thin filaments slide past myosin thick filaments resulting in sarcomeric length shortening (527). This is a highly regulated process mediated by thin and thick filament accessory proteins.…”

Section: Myosinmentioning

confidence: 99%

Thick Filament Protein Network, Functions, and Disease Association

Wang

Geist

Grogan

et al. 2018

Comprehensive Physiology

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Sarcomeres consist of highly ordered arrays of thick myosin and thin actin filaments along with accessory proteins. Thick filaments occupy the center of sarcomeres where they partially overlap with thin filaments. The sliding of thick filaments past thin filaments is a highly regulated process that occurs in an ATP-dependent manner driving muscle contraction. In addition to myosin that makes up the backbone of the thick filament, four other proteins which are intimately bound to the thick filament, myosin binding protein-C, titin, myomesin, and obscurin play important structural and regulatory roles. Consistent with this, mutations in the respective genes have been associated with idiopathic and congenital forms of skeletal and cardiac myopathies. In this review, we aim to summarize our current knowledge on the molecular structure, subcellular localization, interacting partners, function, modulation via posttranslational modifications, and disease involvement of these five major proteins that comprise the thick filament of striated muscle cells. © 2018 American Physiological Society. Compr Physiol 8:631-709, 2018.

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Section: Myosinmentioning

confidence: 99%

Thick Filament Protein Network, Functions, and Disease Association

Wang

Geist

Grogan

et al. 2018

Comprehensive Physiology

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“…The majority of HCM cases are caused by autosomal dominant mutations targeting mechanical proteins of the sarcomere, the basic contractile unit of cardiomyocytes 5,[8][9] (Figure 1a). In sarcomeres, myosin heads use the energy coming from ATP hydrolysis to extend from the myosin backbone in the thick filaments, establish cross-bridges with the neighboring actin thin filaments and generate ~10-nm power strokes that propel the thin filaments past the thick ones leading to muscle contraction (Figure 1b) 4,8,[10][11][12] . Cardiac myosin-binding protein C (cMyBP-C) is a wellknown negative modulator of sarcomere contraction by complex mechanisms that are not fully understood [13][14][15] .…”

Section: Introductionmentioning

confidence: 99%

Nanomechanical phenotypes in cMyBP-C mutants that cause hypertrophic cardiomyopathy

Suay-Corredera¹,

Pricolo²,

Velázquez-Carreras³

et al. 2020

Preprint

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Hypertrophic cardiomyopathy (HCM) is a disease of the myocardium caused by mutations in sarcomeric proteins with mechanical roles, such as the molecular motor myosin. Around half of the HCM-causing genetic variants target contraction modulator cardiac myosin-binding protein C (cMyBP-C), although the underlying pathogenic mechanisms remain unclear since many of these mutations cause no alterations in protein structure and stability. As an alternative pathomechanism, here we have examined whether pathogenic mutations perturb the nanomechanics of cMyBP-C, which would compromise its modulatory mechanical tethers across sliding actomyosin filaments. Using single-molecule atomic force spectroscopy, we have quantified mechanical folding and unfolding transitions in cMyBP-C mutant domains. Our results show that domains containing mutation R495W are mechanically weaker than wild-type at forces below 40 pN, and that R502Q mutant domains fold faster than wild-type. None of these alterations are found in control, non-pathogenic variants, suggesting that nanomechanical phenotypes induced by pathogenic cMyBP-C mutations contribute to HCM development. We propose that mutation-induced nanomechanical alterations may be common in mechanical proteins involved in human pathologies.

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“…Mechanochemical coupling cycles underlie the workgeneration mechanisms of biological systems, 1 ranging from muscle contraction, 2,3 to adenosine triphosphate (ATP) synthesis, 4 to cargo transport. 5,6 Effective freeenergy transduction, a defining feature of such mechanochemical coupling processes, is realized by the folding and assembly of protein machineries and their highly regulated conformational changes.…”

Section: Introductionmentioning

confidence: 99%

Harvesting Mechanical Work From Folding-Based Protein Engines: From Single-Molecule Mechanochemical Cycles to Macroscopic Devices

Wang

2019

CCS Chem

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Mechanochemical coupling cycles underlie the work-generation mechanisms of biological systems and are realized by highly regulated conformational changes of the protein machineries. However, it has been challenging to utilize protein conformational changes to do mechanical work at the macroscopic level in biomaterials, and it remains elusive to construct macroscopic mechanochemical devices based on molecular-level mechanochemical coupling systems. Here, the authors demonstrate that protein folding can be utilized to realize protein’s mechanochemical cycles at both single-molecule and macroscopic levels. Our results demonstrate, for the first time, the successful harnessing of mechanical work generated by protein folding in a macroscopic protein hydrogel device, and the work generated by protein folding compares favorably with the energy output of molecular motors. Our work bridges a gap between single-molecule and macroscopic levels, and paves the way to utilizing proteins as building blocks to design protein-based artificial muscles and soft actuators.

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Muscle contraction: Sliding filament history, sarcomere dynamics and the two Huxleys

Cited by 30 publications

References 63 publications

Thick Filament Protein Network, Functions, and Disease Association

Thick Filament Protein Network, Functions, and Disease Association

Nanomechanical phenotypes in cMyBP-C mutants that cause hypertrophic cardiomyopathy

Harvesting Mechanical Work From Folding-Based Protein Engines: From Single-Molecule Mechanochemical Cycles to Macroscopic Devices

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