Transient disorder along pathways to amyloid.

High-resolution structures of amyloid fibrils formed from normally-folded proteins have revealed non-native conformations of the polypeptide chains. Attaining these conformations apparently requires transition from the native state via a highly disordered conformation, in contrast to earlier models that posited a role for assembly of partially folded proteins. Modifications or interactions that extend the lifetime or constrain the conformations of these disordered states could act to enhance or suppress amyloid formation. Understanding how the properties of both the folded and transiently disordered structural ensembles influence the process of amyloid formation is a substantial challenge, but research into the properties of intrinsically disordered proteins will deliver important insights.