Functional relationship between calreticulin, calnexin, and the endoplasmic reticulum luminal domain of calnexin

Calnexin is a membrane protein of the endoplasmic reticulum (ER) that funct ions as a molecular chaperone and as a component of the ER quality control machinery. Calreticulin, a soluble analog of calnexin, is thought to posses s similar functions, but these have not been directly demonstrated in vivo. Both proteins contain a lectin site that directs their association with ne wly synthesized glycoproteins. Although many glycoproteins bind to both cal nexin and calreticulin, there are differences in the spectrum of glycoprote ins that each binds. Using a Drosophila expression system and the mouse cla ss I histocompatibility molecule as a model glycoprotein, we found that cal reticulin does possess apparent chaperone and quality control functions, en hancing class I folding and subunit assembly, stabilizing subunits, and imp eding export of assembly intermediates from the ER. Indeed, the functions o f calnexin and calreticulin were largely interchangeable. We also determine d that a soluble form of calnexin (residues 1-387) can functionally replace its membrane-bound counterpart. However, when calnexin was expressed as a soluble protein in L cells, the pattern of associated glycoproteins changed to resemble that of calreticulin. Conversely, membrane-anchored calreticul in bound to a similar set of glycoproteins as calnexin. Therefore, the diff erent topological environments of calnexin and calreticulin are important i n determining their distinct substrate specificities.