Functional Cooperation BetweenBiP and Calreticulin in the Folding Maturation of a Glycoprotein in Trypanosomacruzi

CARLOS A. LABRIOLA, ANA M. VILLAMIL-GIRALDO, ARMANDO J. PARODI AND JULIO J. CARAMELO

MOLECULAR AND BIOCHEMICAL PARASITOLOGY

ELSEVIER SCIENCE BV

Lugar: Amsterdam; Año: 2011 vol. 175 p. 112 - 117

0166-6851

  Proteins may adopt diverse conformations during their folding in vivo, ranging from extended chains when they emerge from the ribosome to compact intermediates near the end of the folding process. Accordingly, a variety of chaperones and folding assisting enzymes have evolved to deal with this diversity. Chaperone selection by a particular substrate depends on the structural features of its folding intermediates. In addition, this process may be modulated by competitive effects between chaperones. Here we address this issue by using TcrCATL (cruzipain, cruzain) as model substrate. TcrCATL is an abundant Trypanosomacruzilysosomal protease and it was the first identified endogenous UDP-Glc:glycoproteinglucosyltransferase (UGGT) substrate. We found that TcrCATL associated sequentially with BiP and calreticulin (CRT) during its folding process. Early, extended conformations were bound to BiP, while more advanced and compact folding intermediates associated to CRT. The interaction between TcrCATL and CRT was impeded by deletion of the UGGT-encoding gene but, similarly to what was observed in wild type cells, in mutant cells TcrCATL associated to BiP only when displaying extended conformations. The absence of TcrCATL-CRT interactions in UGGT null cells resulted in a drastic reduction of TcrCATL folding efficiency and triggered the aggregation of TcrCATL through intermolecular disulfide bonds. These observations show that BiP and CRT activities complement each other to supervise a complete and efficient TcrCATL folding process. The present report shows that the basic tenets of the N-glycan dependent quality control mechanism of glycoprotein folding represent an early evolutionary acquisition.