Mutations and off-pathway aggregation of proteins

The off-pathway aggregation of proteins is a ubiquitous, yet poorly understood, phenomenon. In vitro, aggregation places limits on both protein stability and refolding yields. In vivo, it is responsible for inclusion-body formation in the bacterial production of proteins, as well as amyloid disease and related phenomena in animals. An important common feature of these processes is their sensitivity to point mutations, a feature that offers important clues for understanding controversial aspects of off-pathway aggregation such as its molecular specificity and the nature of the aggregating species. Results of a number of studies illustrate that the sensitivity of aggregation can derive from the ability of a mutation to either (1) facilitate the accumulation of a non-native state that is prone to aggregation, or (2) increase the intrinsic tendency of such a state to aggregate.