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Understanding how CRES amyloid assembles<jats:italic>in vitro<\/jats:italic>may provide clues on how the epididymal amyloid matrix forms<jats:italic>in vivo<\/jats:italic>. We therefore purified full-length CRES under nondenaturing conditions and followed its aggregation from monomer to amyloid under conditions that may approximate those in the epididymal lumen. CRES transitioned into a metastable oligomer that was resistant to aggregation and only over extended time formed higher-ordered amyloids. High protein concentrations facilitated oligomer assembly and also were required to maintain the metastable state since following dilution the oligomer was no longer detected. Similar to other amyloid precursors, the formation of CRES amyloids correlated with a loss of \u03b1-helix and a gain of \u03b2-sheet content. However, CRES is unique in that its amyloids are rich in antiparallel \u03b2-sheets instead of the more common parallel \u03b2-sheets. Taken together, our studies suggest that early metastable oligomers may serve as building blocks for functional amyloid assembly and further reveal that antiparallel \u03b2-sheet-rich amyloids can be functional forms.<\/jats:p>","DOI":"10.1038\/s41598-019-45545-w","type":"journal-article","created":{"date-parts":[[2019,6,25]],"date-time":"2019-06-25T21:52:50Z","timestamp":1561499570000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["The Functional Mammalian CRES (Cystatin-Related Epididymal Spermatogenic) Amyloid is Antiparallel \u03b2-Sheet Rich and Forms a Metastable Oligomer During Assembly"],"prefix":"10.1038","volume":"9","author":[{"given":"Hoa Quynh","family":"Do","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aveline","family":"Hewetson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlyn","family":"Myers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nazmul H.","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary Catherine","family":"Hastert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faraz","family":"M. 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