Journal Article

PUBDB-2021-04331

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Molecular basis of F-actin regulation and sarcomere assembly via myotilin

Kostan, J.Extern*EMBL* ; Pavšič, M. ; Puž, V. ; Schwarz, T. C. ; Drepper, F. ; Molt, S. ; Gräwert, M. A.EMBL* ; Schreiner, C. ; Sajko, S. ; van der Ven, P. F. M. ; onipe, a.Extern* ; Svergun, D. I.EMBL* ; Warscheid, B. ; Konrat, R. ; Fürst, D. O. ; Lenarcic, B. (Corresponding author)Extern*EMBL* ; Djinović-Carugo, K. (Corresponding author)

2021
PLoS Lawrence, KS

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Please use a persistent id in citations: doi:10.1371/journal.pbio.3001148  doi:10.3204/PUBDB-2021-04331

Abstract: 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.

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Contributing Institute(s):

1. EMBL-User (EMBL-User)
2. EMBL (EMBL)

Research Program(s):

1. 6G3 - PETRA III (DESY) (POF4-6G3) (POF4-6G3)
2. DFG project 390939984 - EXC 2189: CIBSS - Centre for Integrative Biological Signalling Studies (390939984) (390939984)

Experiment(s):

1. PETRA Beamline P12 (PETRA III)

Appears in the scientific report 2021

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