Glycoprotein-folding quality control in the endoplasmic reticulum

Abstract

Nearly one third of proteins synthesized by eukaryotic cells belong to the secretory pathway, gaining access to the endoplasmic reticulum (ER) either co- or post-translationally. In the ER disulfide bonds are formed, proteins acquire their native tertiary fold and, if needed, they assemble into oligomeric structures. Numerous chaperones and folding assisting enzymes are in place to ensure the fidelity and efficiency of these processes. In addition, nearly 70 % of the secretory pathway proteins are N-glycosylated by the oligosaccharyltransferase complex in the consensus sequence Asn-X-Ser/Thr, in which X can not be Pro . The consensus sequences are generally modified as they emerge into the ER lumen during protein translocation, although in some cases N-glycosylation may occur post-translationally . N-glycosylation is the most abundant and one of the more drastic protein modifications. Commonly, N-glycans are central players in molecular recognition events, a function particularly suitable for them given their vast compositional and structural diversity. In addition, N-glycans may modulate the biophysical behavior of glycoproteins. For instance, N-glycans may inhibit protein aggregation, may increment the resistance towards proteases and can promote the acquisition of some elements of secondary structure such as turns. Of particular importance is the role of N-glycans during glycoprotein folding in the ER. Here, the N-glycans are used as an epigenetic information platform that reflects the folding status of glycoproteins. This code is generated by a family of glycosyltransferases and glycosidases, that translate the structural features of glycoproteins into particular N-glycan structures. A set of ER-resident lectins "read" this information, and react accordingly by retaining the immature species in the ER and/or promoting their degradation.