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Molecular basis of F-actin regulation and sarcomere assembly via myotilin
Sarcomeres, the basic contractile units of striated muscle cells, contain arrays of thin (actin) and thick (myosin) filaments that slide past each other during contraction. The Ig-like domain-containing protein myotilin provides structural integrity to Z-discs—the boundaries between adjacent sarcome...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062120/ https://www.ncbi.nlm.nih.gov/pubmed/33844684 http://dx.doi.org/10.1371/journal.pbio.3001148 |
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author | Kostan, Julius Pavšič, Miha Puž, Vid Schwarz, Thomas C. Drepper, Friedel Molt, Sibylle Graewert, Melissa Ann Schreiner, Claudia Sajko, Sara van der Ven, Peter F. M. Onipe, Adekunle Svergun, Dmitri I. Warscheid, Bettina Konrat, Robert Fürst, Dieter O. Lenarčič, Brigita Djinović-Carugo, Kristina |
author_facet | Kostan, Julius Pavšič, Miha Puž, Vid Schwarz, Thomas C. Drepper, Friedel Molt, Sibylle Graewert, Melissa Ann Schreiner, Claudia Sajko, Sara van der Ven, Peter F. M. Onipe, Adekunle Svergun, Dmitri I. Warscheid, Bettina Konrat, Robert Fürst, Dieter O. Lenarčič, Brigita Djinović-Carugo, Kristina |
author_sort | Kostan, Julius |
collection | PubMed |
description | Sarcomeres, the basic contractile units of striated muscle cells, contain arrays of thin (actin) and thick (myosin) filaments that slide past each other during contraction. The Ig-like domain-containing protein myotilin provides structural integrity to Z-discs—the boundaries between adjacent sarcomeres. Myotilin binds to Z-disc components, including F-actin and α-actinin-2, but the molecular mechanism of binding and implications of these interactions on Z-disc integrity are still elusive. To illuminate them, we used a combination of small-angle X-ray scattering, cross-linking mass spectrometry, and biochemical and molecular biophysics approaches. We discovered that myotilin displays conformational ensembles in solution. We generated a structural model of the F-actin:myotilin complex that revealed how myotilin interacts with and stabilizes F-actin via its Ig-like domains and flanking regions. Mutant myotilin designed with impaired F-actin binding showed increased dynamics in cells. Structural analyses and competition assays uncovered that myotilin displaces tropomyosin from F-actin. Our findings suggest a novel role of myotilin as a co-organizer of Z-disc assembly and advance our mechanistic understanding of myotilin’s structural role in Z-discs. |
format | Online Article Text |
id | pubmed-8062120 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-80621202021-05-04 Molecular basis of F-actin regulation and sarcomere assembly via myotilin Kostan, Julius Pavšič, Miha Puž, Vid Schwarz, Thomas C. Drepper, Friedel Molt, Sibylle Graewert, Melissa Ann Schreiner, Claudia Sajko, Sara van der Ven, Peter F. M. Onipe, Adekunle Svergun, Dmitri I. Warscheid, Bettina Konrat, Robert Fürst, Dieter O. Lenarčič, Brigita Djinović-Carugo, Kristina PLoS Biol Research Article Sarcomeres, the basic contractile units of striated muscle cells, contain arrays of thin (actin) and thick (myosin) filaments that slide past each other during contraction. The Ig-like domain-containing protein myotilin provides structural integrity to Z-discs—the boundaries between adjacent sarcomeres. Myotilin binds to Z-disc components, including F-actin and α-actinin-2, but the molecular mechanism of binding and implications of these interactions on Z-disc integrity are still elusive. To illuminate them, we used a combination of small-angle X-ray scattering, cross-linking mass spectrometry, and biochemical and molecular biophysics approaches. We discovered that myotilin displays conformational ensembles in solution. We generated a structural model of the F-actin:myotilin complex that revealed how myotilin interacts with and stabilizes F-actin via its Ig-like domains and flanking regions. Mutant myotilin designed with impaired F-actin binding showed increased dynamics in cells. Structural analyses and competition assays uncovered that myotilin displaces tropomyosin from F-actin. Our findings suggest a novel role of myotilin as a co-organizer of Z-disc assembly and advance our mechanistic understanding of myotilin’s structural role in Z-discs. Public Library of Science 2021-04-12 /pmc/articles/PMC8062120/ /pubmed/33844684 http://dx.doi.org/10.1371/journal.pbio.3001148 Text en © 2021 Kostan et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Kostan, Julius Pavšič, Miha Puž, Vid Schwarz, Thomas C. Drepper, Friedel Molt, Sibylle Graewert, Melissa Ann Schreiner, Claudia Sajko, Sara van der Ven, Peter F. M. Onipe, Adekunle Svergun, Dmitri I. Warscheid, Bettina Konrat, Robert Fürst, Dieter O. Lenarčič, Brigita Djinović-Carugo, Kristina Molecular basis of F-actin regulation and sarcomere assembly via myotilin |
title | Molecular basis of F-actin regulation and sarcomere assembly via myotilin |
title_full | Molecular basis of F-actin regulation and sarcomere assembly via myotilin |
title_fullStr | Molecular basis of F-actin regulation and sarcomere assembly via myotilin |
title_full_unstemmed | Molecular basis of F-actin regulation and sarcomere assembly via myotilin |
title_short | Molecular basis of F-actin regulation and sarcomere assembly via myotilin |
title_sort | molecular basis of f-actin regulation and sarcomere assembly via myotilin |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062120/ https://www.ncbi.nlm.nih.gov/pubmed/33844684 http://dx.doi.org/10.1371/journal.pbio.3001148 |
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