{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T13:11:25Z","timestamp":1788959485532,"version":"build-2803163510"},"reference-count":55,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100011094","name":"Public Health Agency of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100011094","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT-178097"],"award-info":[{"award-number":["PJT-178097"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2026,9,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>End-elongation of amyloid fibrils is a prevailing theory to explain prion replication, but direct experimental evidence for this phenomenon is limited by the lack of research tools. To serve as molecular probes for prion fibril termini, here, we designed protein binders against high-resolution structures of infectious prion fibrils using a diffusion-based design model. By generating protein scaffolds around short \u03b2-strand segments from terminal prion rungs, we designed \u03b2-hairpin-interfacing proteins that cap prion fibrils, which we termed PRICAPs. We validated that PRICAPs exhibit binding to prion fibril termini and confirmed the role of prion fibril ends in replication by demonstrating that PRICAPs inhibit prion seeding activity and attenuate prion replication in organotypic cerebellar slice cultures. Collectively, these findings describe a class of prion-capping protein that can be used to probe prion fibril termini and verify that these surfaces contribute to prion replication and infectivity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>\n                      Prions replicate by templating the misfolding of native proteins; however, direct evidence identifying the precise sites of replication has remained limited. Here, we address this gap by developing a new class of rationally designed protein tools that specifically bind and cap the ends of infectious prion fibrils. Using these probes, we demonstrate that fibril termini are replication-competent surfaces required for prion seeding and propagation. By inhibiting these sites, our designed proteins markedly reduce prion replication in a disease-relevant\n                      <jats:italic toggle=\"yes\">ex vivo<\/jats:italic>\n                      system, providing functional validation of the end-elongation model. Beyond resolving a fundamental question in prion biology, this work establishes a generalizable strategy for targeting amyloid fibril ends with high specificity. These findings have broad implications for understanding protein aggregation in neurodegenerative diseases and open new avenues for the development of therapeutics that selectively disrupt pathogenic amyloid propagation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.00831-26","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T13:00:37Z","timestamp":1786971637000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":0,"title":["AI-designed prion-capping proteins provide evidence that prion fibril ends are replication-competent surfaces that contribute to prion seeding activity and infectivity"],"prefix":"10.1128","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9025-8368","authenticated-orcid":false,"given":"Jessy A.","family":"Slota","sequence":"first","affiliation":[{"name":"High Consequence Pathogens Division, National Microbiology Laboratory, Public Health Agency of Canada","place":["Winnipeg, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Kirby","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02gfys938","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemistry, Faculty of Science, University of Manitoba","place":["Winnipeg, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aidan","family":"Van Den Driessche","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02gfys938","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Chemistry, Faculty of Science, University of Manitoba","place":["Winnipeg, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominic M. 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