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The rod\u2010like E subunits bend into \u201chairpins\u201d to bring the fusion loops next to the C\u2010terminal transmembrane (TM) anchors, with the TM\u2010proximal \u201cstem\u201d element zippering the E trimer to force apposition of the membranes. The structure of the complete class II trimeric hairpin is known for phleboviruses but not for flaviviruses, for which the stem is only partially resolved. Here, we performed comparative analyses of E\u2010protein trimers from the tick\u2010borne encephalitis flavivirus with sequential stem truncations. Our thermostability and antibody\u2010binding data suggest that the stem \u201czipper\u201d ends at a characteristic flavivirus conserved sequence (CS) that cloaks the fusion loops, with the downstream segment not contributing to trimer stability. We further identified a highly dynamic behavior of E trimers C\u2010terminally truncated upstream the CS, which, unlike fully stem\u2010zippered trimers, undergo rapid deuterium exchange at the trimer interface. These results thus identify important \u201cbreathing\u201d intermediates in the E\u2010protein\u2010driven membrane fusion process.<\/jats:p>","DOI":"10.15252\/embr.202050069","type":"journal-article","created":{"date-parts":[[2020,6,2]],"date-time":"2020-06-02T06:27:05Z","timestamp":1591079225000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Extensive flavivirus E trimer breathing accompanies stem zippering of the post\u2010fusion hairpin"],"prefix":"10.1038","volume":"21","author":[{"given":"Iris","family":"Medits","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie\u2010Christine","family":"Vaney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Rouvinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martial","family":"Rey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Chamot\u2010Rooke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9953-7988","authenticated-orcid":false,"given":"Felix A","family":"Rey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7191-4331","authenticated-orcid":false,"given":"Franz X","family":"Heinz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1902-8674","authenticated-orcid":false,"given":"Karin","family":"Stiasny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,6,2]]},"reference":[{"key":"BFEMBR202050069_CR1","first-page":"747","volume-title":"Fields Virology","author":"TC Pierson","year":"2013","unstructured":"Pierson TC, Diamond MS (2013) Flaviviruses. 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