Structure of an Intermediate State in Protein Folding and Aggregation

Protein Tipping Point Amyloid fibrils are insoluble protein aggregates that play a role in various degenerative diseases. Recent experiments have provided insight into fibrillar structures; however, the mechanisms of aggregation remain unclear. Neudecker et al. (p. 362 ; see the Perspective by Eliezer ) report the structure of a transient folding intermediate in a protein SH3 domain known to undergo aggregation. The intermediate is stabilized by non-native interactions and exposes an aggregation-prone β strand. Thus, for this protein, folding from the intermediate state will compete with aggregation.