Post-translational modification and folding of secreted proteins.

The production of a functional protein does not end with the termination of the growing polypeptide chain. This, while clearly true of all proteins, is particularly obvious in the case of secretory proteins. While all proteins must fold to a functional conformation, and many must assemble into some supramolecular structure, secretory proteins must also make their way across membranes and through secretory compartments. In the course of this secretory pathway, most proteins undergo further chemical modification, so that the covalent structure of the ultimate functional protein is significantly different from that of the initial translation product. Some of these post-translational chemical modifications are ubiquitous in secretory proteins. Thus (with a single known exception, ovalbumin) all secretory proteins undergo cleavage of an N-terminal secretory signal sequence, and in most cases the Cys residues of the initial translation product are paired and oxidized to form disulphide bonds; glycosylation of asparagine, serine and threonine side-chains, and subsequent processing of oligosaccharide side-chains, leads to formation of very complex Nand 0-linked oligosaccharide structures in the majority of secretory and cell-surface proteins. Other modifications are limited to small families of proteins. Selective proteolysis is a common post-translational modification, which does not generate novel amino acid derivatives. Apart from the cotranslational cleavage of the N-terminal secretory signal sequence (Hortsch & Meyer, 1986), secretory proteins often undergo proteolysis at a late stage before secretion, either by endoproteolytic cleavage specifically at paired basic residues (Geisow & Smyth, 1980) or through stepwise removal of N-terminal dipeptides (Kreil et al., 1980). These processes are observed in insects and yeast as well as vertebrates (Kreil, 1985). Some modifications act not on amino-acyl side-chains, but on the Nand C-terminal amino and carboxyl groups. Many polypeptides are N-terminally acylated, either by acetylor fatty acyl groups. N-Terminal acetylation is quite common and is known to be a cotranslational process occurring on nascent chains of 20-50 residues; it is generally found in intracellular proteins, but is also observed in ovalbumin and membrane proteins which lack the cleavable N-terminal signal sequence (Tsunasawa & Sakiyama, 1984). N-Terminal palmitylation is observed in some bacterial membrane proteins, and N-terminal myristylation in a small number of intracellular eukaryotic proteins (Aitken & Cohen, 1984; Henderson el at., 1983). A C-terminal amide group is found in a large number of neuropeptides and other small peptide hormones, and this is now known to be formed from a Cterminal Gly which is removed in the reaction Xaa-CO-NHCH,COOXaa-CO-NH,. Frequently, but not universally, the C-terminal Gly is itself the product of previous proteo-