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Striated Muscle Regulatory Proteins: Function Follows Structure
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Striated Muscle Regulatory Proteins: Function Follows Structure

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 5370

Special Issue Editor

Dr. Natalia Koubassova

E-Mail Website
Guest Editor
Institute of Mechanics, Lomonosov Moscow University, Moscow 119991, Russia
Interests: muscle biophysics; muscle contraction; X-ray diffraction on muscle; mathematical modelling; actin; myosin; tropomyosin; super-relaxed state

Special Issue Information

Dear Colleagues,

Our understanding of the structure and function of the striated muscle regulatory proteins troponin and tropomyosin is extending continuously. Recent cryo-electron microscopy data uncovered new details of the structure of the regulatory complex of the thin filament. Each troponin complex was found to interact with both tropomyosin strands on the opposite sides of the actin filament, possibly providing high cooperativity of the Ca2+ regulation of contraction. Another source of structural information are studies of the point mutation effects in the regulatory proteins. Some mutations were proved to lead to myopathy or cardiomyopathy, while the significance of many others remains unknown. Deep knowledge of the molecular processes involved in the mechanism of muscle regulation will be helpful for future clinical applications.

This Special Issue focuses on recent biomolecular studies investigating tight links between the structure and function of troponin and tropomyosin in striated muscle, with a special aim to elucidate new details of the molecular mechanism of their action. Studies providing new information about how the structural features of these regulatory proteins determine their role in switching muscle on and off are welcomed. The studies may also include clinical data or a pure theoretical approach if they fall within the scope of the Issue.

Dr. Natalia Koubassova
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • muscle
  • muscle regulation
  • troponin
  • tropomyosin
  • thin filament

Published Papers (4 papers)

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Research

12 pages, 2182 KiB  
Article
Troponin and a Myopathy-Linked Mutation in TPM3 Inhibit Cofilin-2-Induced Thin Filament Depolymerization
by Katarzyna Robaszkiewicz, Julia Wróbel and Joanna Moraczewska
Int. J. Mol. Sci. 2023, 24(22), 16457; https://doi.org/10.3390/ijms242216457 - 17 Nov 2023
Viewed by 928
Abstract
Uniform actin filament length is required for synchronized contraction of skeletal muscle. In myopathies linked to mutations in tropomyosin (Tpm) genes, irregular thin filaments are a common feature, which may result from defects in length maintenance mechanisms. The current work investigated the effects [...] Read more.
Uniform actin filament length is required for synchronized contraction of skeletal muscle. In myopathies linked to mutations in tropomyosin (Tpm) genes, irregular thin filaments are a common feature, which may result from defects in length maintenance mechanisms. The current work investigated the effects of the myopathy-causing p.R91C variant in Tpm3.12, a tropomyosin isoform expressed in slow-twitch muscle fibers, on the regulation of actin severing and depolymerization by cofilin-2. The affinity of cofilin-2 for F-actin was not significantly changed by either Tpm3.12 or Tpm3.12-R91C, though it increased two-fold in the presence of troponin (without Ca2+). Saturation of the filament with cofilin-2 removed both Tpm variants from the filament, although Tpm3.12-R91C was more resistant. In the presence of troponin (±Ca2+), Tpm remained on the filament, even at high cofilin-2 concentrations. Both Tpm3.12 variants inhibited filament severing and depolymerization by cofilin-2. However, the inhibition was more efficient in the presence of Tpm3.12-R91C, indicating that the pathogenic variant impaired cofilin-2-dependent actin filament turnover. Troponin (±Ca2+) further inhibited but did not completely stop cofilin-2-dependent actin severing and depolymerization. Full article
(This article belongs to the Special Issue Striated Muscle Regulatory Proteins: Function Follows Structure)
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19 pages, 2581 KiB  
Article
Novel Mutation Glu98Lys in Cardiac Tropomyosin Alters Its Structure and Impairs Myocardial Relaxation
by Alexander M. Matyushenko, Victoria V. Nefedova, Anastasia M. Kochurova, Galina V. Kopylova, Natalia A. Koubassova, Anna G. Shestak, Daria S. Yampolskaya, Daniil V. Shchepkin, Sergey Y. Kleymenov, Natalia S. Ryabkova, Ivan A. Katrukha, Sergey Y. Bershitsky, Elena V. Zaklyazminskaya, Andrey K. Tsaturyan and Dmitrii I. Levitsky
Int. J. Mol. Sci. 2023, 24(15), 12359; https://doi.org/10.3390/ijms241512359 - 02 Aug 2023
Viewed by 1212
Abstract
We characterized a novel genetic variant c.292G > A (p.E98K) in the TPM1 gene encoding cardiac tropomyosin 1.1 isoform (Tpm1.1), found in a proband with a phenotype of complex cardiomyopathy with conduction dysfunction and slow progressive neuromuscular involvement. To understand the molecular mechanism [...] Read more.
We characterized a novel genetic variant c.292G > A (p.E98K) in the TPM1 gene encoding cardiac tropomyosin 1.1 isoform (Tpm1.1), found in a proband with a phenotype of complex cardiomyopathy with conduction dysfunction and slow progressive neuromuscular involvement. To understand the molecular mechanism by which this mutation impairs cardiac function, we produced recombinant Tpm1.1 carrying an E98K substitution and studied how this substitution affects the structure of the Tpm1.1 molecule and its functional properties. The results showed that the E98K substitution in the N-terminal part of the Tpm molecule significantly destabilizes the C-terminal part of Tpm, thus indicating a long-distance destabilizing effect of the substitution on the Tpm coiled-coil structure. The E98K substitution did not noticeably affect Tpm’s affinity for F-actin but significantly impaired Tpm’s regulatory properties. It increased the Ca2+ sensitivity of the sliding velocity of regulated thin filaments over cardiac myosin in an in vitro motility assay and caused an incomplete block of the thin filament sliding at low Ca2+ concentrations. The incomplete motility block in the absence of Ca2+ can be explained by the loosening of the Tpm interaction with troponin I (TnI), thus increasing Tpm mobility on the surface of an actin filament that partially unlocks the myosin binding sites. This hypothesis is supported by the molecular dynamics (MD) simulation that showed that the E98 Tpm residue is involved in hydrogen bonding with the C-terminal part of TnI. Thus, the results allowed us to explain the mechanism by which the E98K Tpm mutation impairs sarcomeric function and myocardial relaxation. Full article
(This article belongs to the Special Issue Striated Muscle Regulatory Proteins: Function Follows Structure)
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20 pages, 5353 KiB  
Article
Structural and Functional Properties of Kappa Tropomyosin
by Galina V. Kopylova, Anastasia M. Kochurova, Daria S. Yampolskaya, Victoria V. Nefedova, Andrey K. Tsaturyan, Natalia A. Koubassova, Sergey Y. Kleymenov, Dmitrii I. Levitsky, Sergey Y. Bershitsky, Alexander M. Matyushenko and Daniil V. Shchepkin
Int. J. Mol. Sci. 2023, 24(9), 8340; https://doi.org/10.3390/ijms24098340 - 06 May 2023
Cited by 1 | Viewed by 1184
Abstract
In the myocardium, the TPM1 gene expresses two isoforms of tropomyosin (Tpm), alpha (αTpm; Tpm 1.1) and kappa (κTpm; Tpm 1.2). κTpm is the result of alternative splicing of the TPM1 gene. We studied the structural features of κTpm and its regulatory function [...] Read more.
In the myocardium, the TPM1 gene expresses two isoforms of tropomyosin (Tpm), alpha (αTpm; Tpm 1.1) and kappa (κTpm; Tpm 1.2). κTpm is the result of alternative splicing of the TPM1 gene. We studied the structural features of κTpm and its regulatory function in the atrial and ventricular myocardium using an in vitro motility assay. We tested the possibility of Tpm heterodimer formation from α- and κ-chains. Our result shows that the formation of ακTpm heterodimer is thermodynamically favorable, and in the myocardium, κTpm most likely exists as ακTpm heterodimer. Using circular dichroism, we compared the thermal unfolding of ααTpm, ακTpm, and κκTpm. κκTpm had the lowest stability, while the ακTpm was more stable than ααTpm. The differential scanning calorimetry results indicated that the thermal stability of the N-terminal part of κκTpm is much lower than that of ααTpm. The affinity of ααTpm and κκTpm to F-actin did not differ, and ακTpm interacted with F-actin significantly worse. The troponin T1 fragment enhanced the κκTpm and ακTpm affinity to F-actin. κκTpm differently affected the calcium regulation of the interaction of pig and rat ventricular myosin with the thin filament. With rat myosin, calcium sensitivity of thin filaments containing κκTpm was significantly lower than that with ααTpm and with pig myosin, and the sensitivity did not differ. Thin filaments containing κκTpm and ακTpm were better activated by pig atrial myosin than those containing ααTpm. Full article
(This article belongs to the Special Issue Striated Muscle Regulatory Proteins: Function Follows Structure)
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18 pages, 2968 KiB  
Article
Impact of Troponin in Cardiomyopathy Development Caused by Mutations in Tropomyosin
by Victoria V. Nefedova, Galina V. Kopylova, Daniil V. Shchepkin, Anastasia M. Kochurova, Olga I. Kechko, Vera A. Borzova, Natalia S. Ryabkova, Ivan A. Katrukha, Vladimir A. Mitkevich, Sergey Y. Bershitsky, Dmitrii I. Levitsky and Alexander M. Matyushenko
Int. J. Mol. Sci. 2022, 23(24), 15723; https://doi.org/10.3390/ijms232415723 - 11 Dec 2022
Cited by 2 | Viewed by 1534
Abstract
Tropomyosin (Tpm) mutations cause inherited cardiac diseases such as hypertrophic and dilated cardiomyopathies. We applied various approaches to investigate the role of cardiac troponin (Tn) and especially the troponin T (TnT) in the pathogenic effects of Tpm cardiomyopathy-associated mutations M8R, K15N, A277V, M281T, [...] Read more.
Tropomyosin (Tpm) mutations cause inherited cardiac diseases such as hypertrophic and dilated cardiomyopathies. We applied various approaches to investigate the role of cardiac troponin (Tn) and especially the troponin T (TnT) in the pathogenic effects of Tpm cardiomyopathy-associated mutations M8R, K15N, A277V, M281T, and I284V located in the overlap junction of neighboring Tpm dimers. Using co-sedimentation assay and viscosity measurements, we showed that TnT1 (fragment of TnT) stabilizes the overlap junction of Tpm WT and all Tpm mutants studied except Tpm M8R. However, isothermal titration calorimetry (ITC) indicated that TnT1 binds Tpm WT and all Tpm mutants similarly. By using ITC, we measured the direct KD of the Tpm overlap region, N-end, and C-end binding to TnT1. The ITC data revealed that the Tpm C-end binds to TnT1 independently from the N-end, while N-end does not bind. Therefore, we suppose that Tpm M8R binds to TnT1 without forming the overlap junction. We also demonstrated the possible role of Tn isoform composition in the cardiomyopathy development caused by M8R mutation. TnT1 dose-dependently reduced the velocity of F-actin-Tpm filaments containing Tpm WT, Tpm A277V, and Tpm M281T mutants in an in vitro motility assay. All mutations impaired the calcium regulation of the actin–myosin interaction. The M281T and I284V mutations increased the calcium sensitivity, while the K15N and A277V mutations reduced it. The Tpm M8R, M281T, and I284V mutations under-inhibited the velocity at low calcium concentrations. Our results demonstrate that Tpm mutations likely implement their pathogenic effects through Tpm interaction with Tn, cardiac myosin, or other protein partners. Full article
(This article belongs to the Special Issue Striated Muscle Regulatory Proteins: Function Follows Structure)
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