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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,10,20]]},"abstract":"<jats:p>Molecular chaperones interact with non-native proteins, playing crucial roles in preventing misfolding and in enabling efficient folding in the cellular environment. Trigger factor is a bacterial chaperone that binds to ribosomes, interacting with nascent polypeptides emerging from the ribosome and guiding their early folding steps. In contrast to the central role of the chaperone in promoting folding of newly synthesized proteins, its dynamic interactions with nascent chains emerging from the ribosome remain poorly understood. Here, we use single-molecule fluorescence and optical tweezers approaches to directly observe and characterize trigger factor interactions with a ribosome-bound client protein at increasing chain lengths. We find that trigger factor dwell times on ribosome\u2013nascent chain complexes increase non-monotonically with nascent chain length, and that binding to nascent proteins is best described by a combination of multiple weak, dynamic interactions that are established after the chaperone docks onto the ribosome and evolve during polypeptide elongation. Application of mechanical force perturbs trigger factor binding, supporting a multivalent interaction model. This binding mode may help to stabilize nascent proteins against misfolding while allowing them to dynamically sample conformational space in search of their native structures.<\/jats:p>","DOI":"10.1073\/pnas.2607201123","type":"journal-article","created":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T17:37:33Z","timestamp":1792085853000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Multivalent weak contacts shape chaperone\u2013nascent protein interactions"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-4624-0824","authenticated-orcid":false,"given":"Nandakumar","family":"Rajasekaran","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00za53h95","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biology, Johns Hopkins University","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitri","family":"Toptygin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00za53h95","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biology, Johns Hopkins University","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Wei","family":"Liao","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00za53h95","id-type":"ROR","asserted-by":"publisher"}],"name":"T.C. 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