Calreticulin functions in vitro as a molecular chaperone for both glycosylated and non-glycosylated proteins.

Calreticulin (CRT) is thought to be a molecular chaperone that interacts with glycoproteins exclusively through a lectin site specific for monoglucosylated oligosaccharides. However, this chaperone function has never been directly demonstrated nor is it clear how lectin-oligosaccharide interactions facilitate glycoprotein folding. Using purified components, we show that CRT suppresses the aggregation not only of a glycoprotein bearing monoglucosylated oligosaccharides but also that of non-glycosylated proteins. Furthermore, CRT forms stable complexes with unfolded, non-glycosylated substrates but does not associate with native proteins. ATP and Zn(2+) enhance CRT's ability to suppress aggregation of non- glycoproteins, whereas engagement of its lectin site with purified oligosaccharide attenuates this function. CRT also confers protection against thermal inactivation and maintains substrates in a folding-competent state. We conclude that in addition to being a lectin CRT possesses a polypeptide binding capacity capable of discriminating between protein conformational states and that it functions in vitro as a classical molecular chaperone.