Actin-binding compounds, previously discovered by FRET-based high-throughput screening, differentially affect skeletal and cardiac muscle

Piyali Guhathakurta, Lien A. Phung, Ewa Prochniewicz, Sarah Lichtenberger, Anna Wilson, David D. Thomas

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Actin's interactions with myosin and other actin-binding proteins are essential for cellular viability in numerous cell types, including muscle. In a previous high-throughput time-resolved FRET (TR-FRET) screen, we identified a class of compounds that bind to actin and affect actomyosin structure and function. For clinical utility, it is highly desirable to identify compounds that affect skeletal and cardiac muscle differently. Because actin is more highly conserved than myosin and most other muscle proteins, most such efforts have not targeted actin. Nevertheless, in the current study, we tested the specificity of the previously discovered actin-binding compounds for effects on skeletal and cardiac a-actins as well as on skeletal and cardiac myofibrils. We found that a majority of these compounds affected the transition of monomeric G-actin to filamentous F-actin, and that several of these effects were different for skeletal and cardiac actin isoforms. We also found that several of these compounds affected ATPase activity differently in skeletal and cardiac myofibrils. We conclude that these structural and biochemical assays can be used to identify actin-binding compounds that differentially affect skeletal and cardiac muscles. The results of this study set the stage for screening of large chemical libraries for discovery of novel compounds that act therapeutically and specifically on cardiac or skeletal muscle.

Original languageEnglish (US)
Pages (from-to)14100-14110
Number of pages11
JournalJournal of Biological Chemistry
Volume295
Issue number41
DOIs
StatePublished - Oct 9 2020

Bibliographical note

Funding Information:
Funding and additional information—This work was supported by National Institutes of Health Grants R01AR032961 and R37AG26160 (to D. D. T.) and T32GM008244 and F30AG057108 (to L. A. P.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2020 American Society for Biochemistry and Molecular Biology Inc.. All rights reserved.

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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