The eS-Sence of -SH in the ER

• Published in: Cell 1998-01, Vol.92 (2), p.145-148
• Main Authors: Huppa, J B, Ploegh, H L
• Format: Article
• Language: English
• Subjects: Disulfides - metabolism; Endoplasmic Reticulum - metabolism; Protein Disulfide-Isomerases - metabolism; Protein Folding
• ISSN: 0092-8674
• DOI: 10.1016/S0092-8674(00)80907-1

Most proteins can reach their native folded state spontaneously in the test tube, but do so slowly and inefficiently. In contrast, protein folding in the living cell is remarkably fast and efficient, owing to the guidance provided by molecular chaperones. In eukaryotes, protein folding and S-S bond formation are coupled processes that occur both co- and posttranslationally in the endoplasmic reticulum (ER), the main port of entry for secretory and membrane proteins. Once formed, S-S bonds are considered part of the primary structure of a protein and often maintain the stable folding pattern of proteins that contain them. Two papers in the January issue of Molecular Cell shed new light on the molecular machinery that introduces S-S bonds in vivo. Much of our present understanding of protein folding and the role of S-S bonds therein stems from experiments that examine the refolding in vitro of completely reduced, full length polypeptides. However, a nascent polypeptide chain must acquire not only the proper set of disulfide bonds for attaining its final, functional conformational state. A further set of characteristic modifications occur cotranslationally and require interactions of a series of proteins with the nascent chain that will affect its folding environment. For a mammalian cell, a short catalog would include the following. Cleavable signal peptides are removed from the nascent chain by the action of signal peptidase. N-linked glycans are attached, the enzymatic machinery for which must therefore be in close proximity to the translocation channel. cis-trans isomerization of proline residues, a bottleneck for protein folding in vitro, is catalyzed on nascent polypeptides by the protein prolyl isomerase (PPI). Intrachain S-S bond formation also occurs on the nascent chain. Protein disulfide isomerase (PDI), an abundant ER resident enzyme was reported in close proximity to the nascent chain and is thought to be involved in both the formation and the reshuffling of S-S bonds already present. The ER resident chaperones calnexin and calreticulin bind unfolded substrates in lectin-type fashion, sense the acquisition of a (locally) folded state, and then release them in a manner that involves cycles of deglucosylation and reglucosylation. Again, these interactions are initiated on the nascent chain. Polypeptides do not emerge into the ER at a constant rate, and as shown for ApoB, polypeptides that will ultimately acquire an ER-lumenal disposition may transi