Molecular basis of F-actin regulation and sarcomere assembly via myotilin.

Autor: Kostan J; Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, Vienna, Austria., Pavšič M; Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia., Puž V; Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia., Schwarz TC; Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, Vienna, Austria., Drepper F; Biochemistry and Functional Proteomics, Institute of Biology II, Faculty of Biology, University of Freiburg, Freiburg, Germany.; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany., Molt S; Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Bonn, Germany., Graewert MA; European Molecular Biology Laboratory, Hamburg Unit, c/o DESY, Hamburg, Germany., Schreiner C; Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, Vienna, Austria., Sajko S; Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, Vienna, Austria., van der Ven PFM; Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Bonn, Germany., Onipe A; Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, Vienna, Austria., Svergun DI; European Molecular Biology Laboratory, Hamburg Unit, c/o DESY, Hamburg, Germany., Warscheid B; Biochemistry and Functional Proteomics, Institute of Biology II, Faculty of Biology, University of Freiburg, Freiburg, Germany.; Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany., Konrat R; Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, Vienna, Austria., Fürst DO; Institute for Cell Biology, Department of Molecular Cell Biology, University of Bonn, Bonn, Germany., Lenarčič B; Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia.; Department of Biochemistry, Molecular and Structural Biology, Jožef Stefan Institute, Ljubljana, Slovenia., Djinović-Carugo K; Department of Structural and Computational Biology, Max Perutz Labs, University of Vienna, Vienna, Austria.; Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia.
Jazyk: angličtina
Zdroj: PLoS biology [PLoS Biol] 2021 Apr 12; Vol. 19 (4), pp. e3001148. Date of Electronic Publication: 2021 Apr 12 (Print Publication: 2021).
DOI: 10.1371/journal.pbio.3001148
Abstrakt: 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.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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