National Academy of Sciences, Proceedings of the National Academy of Sciences, 28(117), p. 16363-16372, 2020
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Significance Some amyloids are functional in the normal physiology of cells. Of these, several have been found in complex amyloid matrices that are composed of multiple amyloidogenic precursors. Here we trace the lifecycle of the mouse CRES (cystatin-related epididymal spermatogenic) protein, a functional amyloidogenic precursor and component of a complex amyloid matrix in the epididymis, as it progresses from monomeric folded protein to an advanced amyloid. We discovered that CRES amyloid formation may involve β-sheet assemblies generated by two distinct mechanisms: those formed by a flexible CRES loop and those formed by domain swapping. These mechanisms would provide multiple contact surfaces for further β-sheet assemblies with neighboring proteins resulting in sophisticated quaternary structures which may be integral for biological function.