Calreticulin and Calnexin as Chaperones in Glycoprotein Folding

Abstract

Protein folding efficiency is enhanced in vivo by an array of chaperones and folding-assisting enzymes that cover the entire protein folding pathway, from the exit of the polypeptide from the ribosome, its translocation through membranes, disulfide bond formation, tertiary structure acquisition, and oligomer assembly. A protein acquires diverse conformational states during these processes, from extended and disordered structures when exiting the ribosome to more structured intermediates such as molten globule-like forms. Accordingly, the high diversity of chaperones reflects the conformational variety of their substrates. From a statistical point of view, the native state represents an extremely small fraction of the conformational space available to a protein, which may easily fall into irreversible kinetic traps during the folding process. In this sense, the crowded environment inside a cell represents a hostile scenario for protein folding, where protein aggregation could be the rule rather than the exception. One of the main functions of chaperones, perhaps the most important, is to inhibit nonspecific protein interactions, directing the protein to a productive folding pathway.