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000471053 1001_ $$0P:(DE-H253)PIP1019431$$aKostan, Julius$$b0
000471053 245__ $$aMolecular basis of F-actin regulation and sarcomere assembly via myotilin
000471053 260__ $$aLawrence, KS$$bPLoS$$c2021
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000471053 520__ $$aSarcomeres, 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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000471053 7001_ $$0P:(DE-HGF)0$$aPavšič, Miha$$b1
000471053 7001_ $$0P:(DE-HGF)0$$aPuž, Vid$$b2
000471053 7001_ $$0P:(DE-HGF)0$$aSchwarz, Thomas C.$$b3
000471053 7001_ $$0P:(DE-HGF)0$$aDrepper, Friedel$$b4
000471053 7001_ $$0P:(DE-HGF)0$$aMolt, Sibylle$$b5
000471053 7001_ $$0P:(DE-H253)PIP1016308$$aGräwert, Melissa Ann$$b6
000471053 7001_ $$0P:(DE-HGF)0$$aSchreiner, Claudia$$b7
000471053 7001_ $$0P:(DE-HGF)0$$aSajko, Sara$$b8
000471053 7001_ $$0P:(DE-HGF)0$$avan der Ven, Peter F. M.$$b9
000471053 7001_ $$0P:(DE-H253)PIP1017382$$aonipe, adekunle$$b10
000471053 7001_ $$0P:(DE-H253)PIP1001422$$aSvergun, Dmitri I.$$b11
000471053 7001_ $$0P:(DE-HGF)0$$aWarscheid, Bettina$$b12
000471053 7001_ $$0P:(DE-HGF)0$$aKonrat, Robert$$b13
000471053 7001_ $$0P:(DE-HGF)0$$aFürst, Dieter O.$$b14
000471053 7001_ $$0P:(DE-H253)PIP1095129$$aLenarcic, Brigita$$b15$$eCorresponding author
000471053 7001_ $$0P:(DE-HGF)0$$aDjinović-Carugo, Kristina$$b16$$eCorresponding author
000471053 773__ $$0PERI:(DE-600)2126773-X$$a10.1371/journal.pbio.3001148$$gVol. 19, no. 4, p. e3001148 -$$n4$$pe3001148 (1-34)$$tPLoS biology$$v19$$x1545-7885$$y2021
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