Disulfide bonds: protein folding and subcellular protein trafficking

The study of disulfide-bond-containing proteins has advanced our understanding of the mechanism(s) by which the majority of secretory and membrane-bound proteins acquire their biologically functional folded forms. This covalent linkage has been exploited by a number of research laboratories to harness or trap intermediates populating the folding trajectories of biopolymers. The resulting body of gathered in vitro data demonstrates that, in general, there is a common event underscoring the maturation of disulfide-bond-containing proteins. This commonality is the existence of competition between a physical, conformational folding reaction and a chemical, thiol-disulfide exchange reaction during fold acquisition. The competition, in turn, impacts the fate of the polypeptide in being secreted or retrotranslocated. The role of a host of subcellular factors, including protein disulfide isomerase, that influences this critical spatiotemporal juncture of the fold-maturation process is discussed. Finally, the impact of this competition on the onset of neurodegenerative disorders is elaborated upon.