Fascin structural plasticity mediates flexible actin bundle construction.

Autor:	Gong R; Laboratory of Structural Biophysics and Mechanobiology, The Rockefeller University, New York, NY, USA., Reynolds MJ; Laboratory of Structural Biophysics and Mechanobiology, The Rockefeller University, New York, NY, USA., Carney KR; Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.; Department of Biomedical Engineering, University of Utah, Salt Lake City, Utah, USA., Hamilton K; Laboratory of Structural Biophysics and Mechanobiology, The Rockefeller University, New York, NY, USA., Bidone TC; Department of Biomedical Engineering, University of Utah, Salt Lake City, Utah, USA., Alushin GM; Laboratory of Structural Biophysics and Mechanobiology, The Rockefeller University, New York, NY, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Feb 10. Date of Electronic Publication: 2024 Feb 10.
DOI:	10.1101/2024.01.03.574123
Abstrakt:	Fascin crosslinks actin filaments (F-actin) into bundles that support tubular membrane protrusions including filopodia and stereocilia. Fascin dysregulation drives aberrant cell migration during metastasis, and fascin inhibitors are under development as cancer therapeutics. Here, we use cryo-electron microscopy, cryo-electron tomography coupled with custom denoising, and computational modeling to probe fascin's F-actin crosslinking mechanisms across spatial scales. Our fascin crossbridge structure reveals an asymmetric F-actin binding conformation that is allosterically blocked by the inhibitor G2. Reconstructions of seven-filament hexagonal bundle elements, variability analysis, and simulations show how structural plasticity enables fascin to bridge varied inter-filament orientations, accommodating mismatches between F-actin's helical symmetry and bundle hexagonal packing. Tomography of many-filament bundles and modeling uncovers geometric rules underlying emergent fascin binding patterns, as well as the accumulation of unfavorable crosslinks that limit bundle size. Collectively, this work shows how fascin harnesses fine-tuned nanoscale structural dynamics to build and regulate micron-scale F-actin bundles. Competing Interests: Declaration of Interests The authors have no competing interests to declare.
Databáze:	MEDLINE
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