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| Title | Fascin structural plasticity mediates flexible actin bundle construction. |
|---|---|
| Journal, issue, pages | Nat Struct Mol Biol, Vol. 32, Issue 5, Page 940-952, Year 2025 |
| Publish date | Jan 20, 2025 |
Authors | Rui Gong / Matthew J Reynolds / Keith R Carney / Keith Hamilton / Tamara C Bidone / Gregory M Alushin / ![]() |
| PubMed Abstract | Fascin cross-links actin filaments (F-actin) into bundles that support tubular membrane protrusions including filopodia and stereocilia. Fascin dysregulation drives aberrant cell migration during ...Fascin cross-links 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-EM, cryo-electron tomography coupled with custom denoising and computational modeling to probe human fascin-1's F-actin cross-linking mechanisms across spatial scales. Our fascin cross-bridge 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 interfilament orientations, accommodating mismatches between F-actin's helical symmetry and bundle hexagonal packing. Tomography of many-filament bundles and modeling uncover geometric rules underlying emergent fascin binding patterns, as well as the accumulation of unfavorable cross-links 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. |
External links | Nat Struct Mol Biol / PubMed:39833469 / PubMed Central |
| Methods | EM (single particle) / EM (subtomogram averaging) |
| Resolution | 3.0 - 12.0 Å |
| Structure data | EMDB-43364, PDB-8vo5: EMDB-43365, PDB-8vo6: EMDB-43366, PDB-8vo7: EMDB-43367, PDB-8vo8: EMDB-43368, PDB-8vo9: EMDB-43369, PDB-8voa: ![]() EMDB-43370: Fascin crosslinked F-actin hexagonal bundle element (460 Angstrom box) ![]() EMDB-43371: Fascin crosslinked F-actin hexagonal bundle element (740 Angstrom box) ![]() EMDB-43372: Subtomogram averaging structure of fascin bound to F-actin ![]() EMDB-43764: cryo-EM structure of fascin crosslinked F-actin (containing both actin binding sites) |
| Chemicals | ![]() ChemComp-ADP: ![]() ChemComp-MG: |
| Source |
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Keywords | STRUCTURAL PROTEIN / Cytoskeleton / F-actin crosslinker / F-actin bundle |
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homo sapiens (human)
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