Quality Control in Glycoprotein Folding

Abstract

The concept of quality control of protein folding in the secretory pathway emerged in the late 1970s and early 1980s when it was noticed that not in all cases did insertion of proteins in the endoplasmic reticulum (ER) result in their appearance at the expected final destination, intra- or extracellular. Several experimental results showed that cells displayed mechanisms that ensured that only proteins in their native conformations could be produced by the secretory pathway. Those mechanisms received the collective denomination of ‘‘quality control’’. Protein folding in living cells is a complex, error-prone process. Numerous mechanisms are in place to ensure that newly synthesized proteins reach their folded functional form. One such mechanism is the addition of glycans occurring in the ER lumen. Covalently linked N-glycans affect protein folding in cell-free assays, as they provide bulky, highly hydrophilic substituents that maintain molecules in solution while protein moieties successively adopt a variety of different conformations before reaching their final structures. In addition, the highly hydrophilic nature of N-glycans forces the asparagine units to which they are linked and neighboring amino acids to be in or close to the water-protein interphase. This chapter will not deal with those effects, which certainly also occur in vivo, but with folding-efficiency enhancement and ER retention of folding intermediates and irreparably misfolded species mediated by the interaction of a specific glycan structure (monoglucosylated polymannose-type compounds) with the ER lectins calnexin (CNX) and calreticulin (CRT). Recent evidence suggesting a role for a specific putative lectin (EDEM/Htm1p/Man1p) on the disposal of irreparably misfolded glycoproteins will be discussed also.