Thick Filament Protein Network, Functions, and Disease Association

Wang, Li; Geist, Janelle; Grogan, Alyssa; Hu, Li-Yen R.; Kontrogianni‐Konstantopoulos, Aikaterini

doi:10.1002/cphy.c170023

Cited by 62 publications

(53 citation statements)

References 628 publications

(1,270 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Based on a few structural studies of smooth muscle [ 25 ] and larger knowledge of skeletal muscle [ 26 ], a plausible model of filament structure was predicted. Through the influence of a recent imaging study of cell culture of differentiated smooth muscle cells [ 27 ], the elements of the contractile unit were made using two broom-like bundles of actin filaments. The animated structure directly provides understanding of the motility mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Modeling a Microtubule Filaments Mesh Structure from Confocal Microscopy Imaging

et al. 2020

View full text Add to dashboard Cite

This study introduces a modeling method for a supermolecular structure of microtubules for the development of a force generation material using motor proteins. 3D imaging by confocal laser scanning microscopy (CLSM) was used to obtain 3D volume density data. The density data were then interpreted by a set of cylinders with the general-purpose 3D modeling software Blender, and a 3D network structure of microtubules was constructed. Although motor proteins were not visualized experimentally, they were introduced into the model to simulate pulling of the microtubules toward each other to yield shrinking of the network, resulting in contraction of the artificial muscle. From the successful force generation simulation of the obtained model structure of artificial muscle, the modeling method introduced here could be useful in various studies for potential improvements of this contractile molecular system.

show abstract

Section: Discussionmentioning

confidence: 99%

Modeling a Microtubule Filaments Mesh Structure from Confocal Microscopy Imaging

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Although most of the compounds in the present study have been used to treat non-contractile dysfunction in humans (as anti-cancer, anti-psychotic, and anti-malarial agents), it is possible that some of them, or derivatives of them, have therapeutic potential for cardiomyopathy where attenuation of contractility is beneficial, as in a hypercontractile state caused by HCM mutations in myosin or actin (38,39). Regulation of striated muscle contractility is not only thin-filament dependent, but also thick-filament dependent, whereby the myosin binding affinity to actin is attenuated via phosphorylation of the light chains (40) and myosin-binding protein C (41,42), changes in flexibility and conformation (LC domain (43), converter region (44), actin binding region (3,45), and small molecules (Mava and OM) (39) that affect the myosin ATPase cycle. In the present study, we have shown that the compounds increase ATP affinity and decrease the rate constant for the subsequent isomerization steps in ternary complex formation (and hence the release of S1 from actin), which is likely to produce actin-bound non-force producing heads, resulting in decreased ATPase activity.…”

Section: Potential Therapeutic Applicationsmentioning

confidence: 99%

Actin-binding compounds that affect the kinetics of the interaction of cardiac myosin with actin

Roopnarine

Thomas

2020

Preprint

View full text Add to dashboard Cite

We measured the effects of ten actin-binding compounds on the interaction of cardiac myosin subfragment 1 (S1) with pyrene labeled F-actin (PFA). These compounds, previously identified from a small-molecule high-throughput screen (HTS), perturb the microsecond structural dynamics of actin and the steady-state activity of actin-activated myosin ATPase. In the present study, we have further characterized their mechanisms of action by measuring their effects on PFA fluorescence, which is decreased specifically by the strong binding of myosin to actin, and is restored upon release of S1 by MgATP. We measured the effects of compounds under equilibrium and steady-state conditions, as affected by S1 and ATP, and also under transient conditions, in stopped-flow experiments following rapid addition of ATP to S1-bound PFA. We observe that these compounds affect the early steps of the myosin ATPase cycle to different extents (mild, moderate, and severe). The compounds decrease the equilibrium constant for the formation of the collision complex and the rate constant for subsequent isomerization to the ternary complex, indicating increased ATP affinity and trapping of ATP in the myosin active site. These compound effects on actin structure inhibit the kinetics of the actin-myosin interaction in ways that may be desirable for possible treatment of hypercontractile forms of hypertrophic cardiomyopathy (HCM). This work helps to elucidate the mechanisms of action of these compounds, several of which are currently used therapeutically, and it sets the stage for future HTS campaigns on a larger scale, to discover new drugs for treatment of heart failure.

show abstract

“…The most thoroughly studied inherited myopathies are the cardiomyopathies, particularly hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) [ 8 , 10 , 11 , 12 , 13 , 14 ]. DCM accounts for 30–40% of heart failure and is the second commonest cause after coronary artery disease.…”

Section: From Clinic To Fundamental Studiesmentioning

confidence: 99%

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

Marston

2018

IJMS

View full text Add to dashboard Cite

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.

show abstract

Thick Filament Protein Network, Functions, and Disease Association

Cited by 62 publications

References 628 publications

Modeling a Microtubule Filaments Mesh Structure from Confocal Microscopy Imaging

Modeling a Microtubule Filaments Mesh Structure from Confocal Microscopy Imaging

Actin-binding compounds that affect the kinetics of the interaction of cardiac myosin with actin

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

Contact Info

Product

Resources

About