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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\u2019s 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\u2019s 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.<\/jats:p>","DOI":"10.1038\/s41594-024-01477-2","type":"journal-article","created":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T05:04:51Z","timestamp":1737349491000},"page":"940-952","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Fascin structural plasticity mediates flexible actin bundle construction"],"prefix":"10.1038","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7270-2974","authenticated-orcid":false,"given":"Rui","family":"Gong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2501-9280","authenticated-orcid":false,"given":"Matthew J.","family":"Reynolds","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3508-6313","authenticated-orcid":false,"given":"Keith R.","family":"Carney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Hamilton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara C.","family":"Bidone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7250-4484","authenticated-orcid":false,"given":"Gregory M.","family":"Alushin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,20]]},"reference":[{"key":"1477_CR1","doi-asserted-by":"publisher","first-page":"1110","DOI":"10.1038\/ncb1007-1110","volume":"9","author":"ES Chhabra","year":"2007","unstructured":"Chhabra, E. 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