Mutations Affecting Protein Folding and Misfolding in Vivo

Abstract

In vivo folding and in vitro refolding studies of many proteins have established that the polypeptide chain does not attain the native conformation directly, but must pass through partially folded intermediates, (Creighton 1978, Kim and Baldwin 1982, Goldenberg and King 1982). It has often been assumed that such species are conformational subsets of the fully folded native state. In fact the existing data suggest that folding intermediates have properties of their own, not necessarily reflected in the native state (Creighton and Goldenberg, 1984). Numerous cases have now been described in which partially folded intermediates form transient complexes with helper proteins, (chaperonins) within the cells, (Pelham 1986, Hemmingsen et al. 1988, Goloubinoff et al. 1989a, b). The necessity of proteins to fold in physiological environments can explain why intermediates might have distinct properties from those of the native state. These chains may have specific sites and properties that can mediate recognition with molecular chaperones, membrane transport sites and other factors. For proteins destined to be exported through a membrane channel, the chain must be prevented from prematurely reaching the native conformation, (Randall and Hardy, 1988). Thus, folding intermediates must have been evolved with respect to their in vivo folding environments.