Studying the folding of multidomain proteins

Abstract

There have been relatively few detailed comprehensive studies of the folding of protein domains (or modules) in the context of their natural covalently linked neighbors. This is despite the fact that a significant proportion of the proteome consists of multidomain proteins. In this review we highlight some key experimental investigations of the folding of multidomain proteins to draw attention to the difficulties that can arise in analyzing such systems. The evidence suggests that interdomain interactions can significantly affect stability, folding, and unfolding rates. However, preliminary studies suggest that folding pathways are unaffected-to this extent domains can be truly considered to be independent folding units. Nonetheless, it is clear that interactions between domains cannot be ignored, in particular when considering the effects of mutations.