Molecular characterization of linker and loop-mediated structural modulation and hinge motion in the C4-C5 domains of cMyBPC

Doh, Chang Yoon; Bharambe, Nikhil; Holmes, Joshua B.; Dominic, Katherine L.; Swanberg, Caitlin E.; Mamidi, Ranganath; Chen, Yinghua; Bandyopadhyay, Smarajit; Ramachandran, Rajesh; Stelzer, Julian E.

doi:10.1016/j.jsb.2022.107856

Cited by 7 publications

(15 citation statements)

References 81 publications

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“…Several studies have shown that MyBPC is a dynamic molecule with internal hinges that permit a wide range of motion ( Colson et al, 2016 ; Previs et al, 2016 ). Although the N-terminal domains primarily have been shown to influence actin binding and rotational dynamics, it is hypothesized that the central domains’ internal hinge (C4-C5) may also contribute to this action ( Colson et al, 2016 ; Nadvi et al, 2016 ; Doh et al, 2022a ). More recently, a “hinge-and-latch” mechanism was proposed to explain the biophysical properties of this region through molecular dynamics simulations ( Doh et al, 2022a ).…”

Section: Arrangement and Dynamics Of The Central Domains Of Mybpcmentioning

confidence: 99%

“…Although the N-terminal domains primarily have been shown to influence actin binding and rotational dynamics, it is hypothesized that the central domains’ internal hinge (C4-C5) may also contribute to this action ( Colson et al, 2016 ; Nadvi et al, 2016 ; Doh et al, 2022a ). More recently, a “hinge-and-latch” mechanism was proposed to explain the biophysical properties of this region through molecular dynamics simulations ( Doh et al, 2022a ). By creating constructs with deletions in the linker and loop regions, the authors showed that the C4-C5 linker aids in reducing the C4 and C5 interdomain angles (acting as a “hinge”), while the C5 loop region helps form sustained interdomain interactions in the presence of the linker region (acting as the “latch”).…”

Section: Arrangement and Dynamics Of The Central Domains Of Mybpcmentioning

confidence: 99%

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Bringing into focus the central domains C3-C6 of myosin binding protein C

Doh,

Schmidt,

Chinthalapudi

et al. 2024

Front. Physiol.

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Myosin binding protein C (MyBPC) is a multi-domain protein with each region having a distinct functional role in muscle contraction. The central domains of MyBPC have often been overlooked due to their unclear roles. However, recent research shows promise in understanding their potential structural and regulatory functions. Understanding the central region of MyBPC is important because it may have specialized function that can be used as drug targets or for disease-specific therapies. In this review, we provide a brief overview of the evolution of our understanding of the central domains of MyBPC in regard to its domain structures, arrangement and dynamics, interaction partners, hypothesized functions, disease-causing mutations, and post-translational modifications. We highlight key research studies that have helped advance our understanding of the central region. Lastly, we discuss gaps in our current understanding and potential avenues to further research and discovery.

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Section: Arrangement and Dynamics Of The Central Domains Of Mybpcmentioning

confidence: 99%

Section: Arrangement and Dynamics Of The Central Domains Of Mybpcmentioning

confidence: 99%

Bringing into focus the central domains C3-C6 of myosin binding protein C

Doh,

Schmidt,

Chinthalapudi

et al. 2024

Front. Physiol.

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“…These regions are believed to be disordered and likely correspond to the linkers connecting MyBPC3’s folded domains. Doh et al (2022) showed that the flexible linker connecting the C4 and C5 domains of MyBPC3 not only modulates the secondary structure content in the C4 and C5 domains, but also affects their relative interdomain orientations and associated kinetics ( Doh et al, 2022 ). By using MD simulations, they pinpointed specific residue–residue contacts, and the local conformation changes of the linker, that contribute to its modulatory role.…”

Section: Myofilament-associated Protein With Intrinsic Disorder (Mapid)smentioning

confidence: 99%

Myofilament-associated proteins with intrinsic disorder (MAPIDs) and their resolution by computational modeling

Sun

Kekenes‐Huskey

2023

Quart. Rev. Biophys.

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The cardiac sarcomere is a cellular structure in the heart that enables muscle cells to contract. Dozens of proteins belong to the cardiac sarcomere, which work in tandem to generate force and adapt to demands on cardiac output. Intriguingly, the majority of these proteins have significant intrinsic disorder that contributes to their functions, yet the biophysics of these intrinsically disordered regions (IDRs) have been characterized in limited detail. In this review, we first enumerate these myofilament-associated proteins with intrinsic disorder (MAPIDs) and recent biophysical studies to characterize their IDRs. We secondly summarize the biophysics governing IDR properties and the state-of-the-art in computational tools toward MAPID identification and characterization of their conformation ensembles. We conclude with an overview of future computational approaches toward broadening the understanding of intrinsic disorder in the cardiac sarcomere.

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“…Misfolded proteins can derail proteostasis by aggregateformation, local cleavage or accelerated protein turnover (56). Stability of solubly expressed protein domains can be directly assessed in a high throughput manner via differential scanning fluorimetry (DSF) in either 96-or 384-well format, which allows for the identification of variants that likely alter domain folding by changes in the observable melting temperature (57)(58)(59)(60). Initial "hits" in DSF screen can subsequently be confirmed using orthogonal methods such as circular dichroism (CD) spectroscopy, which can give additional information of changes in protein secondary and tertiary structure.…”

Section: High Throughput In Vitro Screening Tools For Rapid Character...mentioning

confidence: 99%

Basic science methods for the characterization of variants of uncertain significance in hypertrophic cardiomyopathy

Doh,

Kampourakis,

Campbell

et al. 2023

Front. Cardiovasc. Med.

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With the advent of next-generation whole genome sequencing, many variants of uncertain significance (VUS) have been identified in individuals suffering from inheritable hypertrophic cardiomyopathy (HCM). Unfortunately, this classification of a genetic variant results in ambiguity in interpretation, risk stratification, and clinical practice. Here, we aim to review some basic science methods to gain a more accurate characterization of VUS in HCM. Currently, many genomic data-based computational methods have been developed and validated against each other to provide a robust set of resources for researchers. With the continual improvement in computing speed and accuracy, in silico molecular dynamic simulations can also be applied in mutational studies and provide valuable mechanistic insights. In addition, high throughput in vitro screening can provide more biologically meaningful insights into the structural and functional effects of VUS. Lastly, multi-level mathematical modeling can predict how the mutations could cause clinically significant organ-level dysfunction. We discuss emerging technologies that will aid in better VUS characterization and offer a possible basic science workflow for exploring the pathogenicity of VUS in HCM. Although the focus of this mini review was on HCM, these basic science methods can be applied to research in dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM), arrhythmogenic cardiomyopathy (ACM), or other genetic cardiomyopathies.

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Molecular characterization of linker and loop-mediated structural modulation and hinge motion in the C4-C5 domains of cMyBPC

Cited by 7 publications

References 81 publications

Bringing into focus the central domains C3-C6 of myosin binding protein C

Bringing into focus the central domains C3-C6 of myosin binding protein C

Myofilament-associated proteins with intrinsic disorder (MAPIDs) and their resolution by computational modeling

Basic science methods for the characterization of variants of uncertain significance in hypertrophic cardiomyopathy

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