Protein folding in the endoplasmic reticulum

Abstract

In this article, we will cover the folding of proteins in the lumen of the endoplasmic reticulum (ER), including the role of three types of covalent modifications: signal peptide removal, N-linked glycosylation, and disulfide bond formation, as well as the function and importance of resident ER folding factors. These folding factors consist of classical chaperones and their cochaperones, the carbohydrate-binding chaperones, and the folding catalysts of the PDI and proline cis-trans isomerase families. We will conclude with the perspective of the folding protein: a comparison of characteristics and folding and exit rates for proteins that travel through the ER as clients of the ER machinery.

Figure 1.

Parallel events during protein folding. The gray bar represents a time course, where folding starts during translation and continues until the protein has reached its native conformation and leaves the ER. If not properly folded or assembled it may exit as misfolded protein.

Figure 2.

Co- and posttranslational protein folding in the ER lumen. Top panel, the ribosome (grey) sits on the Sec61 translocon (orange) to support cotranslational translocation of the nascent chain into the ER lumen. The oligosaccharyltransferase (OST) attaches preassembled glycans (tree structure) to Asn on the nascent chain. BiP (green) and PDI (purple) are positioned for early assistance. Disulfide bonds start to form. The amino-terminal signal sequence is cleaved by the signal sequence peptidase complex (SPC, light blue). Glucosidase I (GlsI) removes the terminal glucose residue (orange triangle) from the N-linked glycan. The diglucosylated glycan can bind to the membrane-associated lectin, malectin (dark blue). Glucosidase II (GlsII) removes a second glucose to generate a monoglucosylated glycan structure that is bound to calnexin (CNX, green), a lectin chaperone associated with the oxidoreductase ERp57 (pink). Lectin chaperone binding continues until GlsII removes the final glucose residue. Bottom panel, the listed factors interact co- and posttranslationally, after the translation of the nascent chain has been completed. These factors help with maturation and the sorting of the native or nonnative protein for its various fates. Calreticulin (CRT) is a soluble paralogue of calnexin.