biostudies-literatureKostan JGermany Excellence StrategyAustrian Science Fund FWFInterregDeutsche ForschungsgemeinschaftFP7 People: Marie-Curie ActionsSlovenian Research AgencyVienna Science and Technology FundAustrian Federal Ministry of Economy, Family and YouthWellcome Truste3001148https://www.ebi.ac.uk/biostudies/studies/S-EPMC8062120biostudies-literatureUnknown19(4)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 rPLoS biologyMolecular basis of F-actin regulation and sarcomere assembly via myotilin.PMC8062120238423201543FOR 1352, FOR 2743Collaborative Award (201543/Z/16)I525, I1593, P22276, P19060 and W122135337, P1-0140I 525253275Chemical Biology project LS17-008201543/Z/16390939984I 1593Austrian-Slovak Interreg Project B301Sajko Svan der Ven PFMKostan JDjinovic-Carugo KPavsic MMolt SDrepper FSvergun DILenarcic BSchwarz TCGraewert MAPuz VKonrat RFurst DOWarscheid BOnipe ASchreiner CfalseMolecular 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 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 r2021-01-01T00:00:00Z2021 Apr2026-05-09T08:49:13.095Z2022-02-10T09:23:27.356ZS-EPMC80621203384468410.1371/journal.pbio.3001148