ATP Acts as Switch for Toggling Calreticulin Between its Lectin and Chaperone Function

Abstract

Calreticulin (CRT) is a lectin-binding chaperone that plays an important role in the assembly and folding of the major histocompatibility complex (MHC) class I proteins that present antigenic peptides on the cell surface and enable their recognition by T-cells. CRT binds to both specific oligosaccharide structures on MHC class I during their folding as well as a polypeptide part of MHC and thus plays a crucial role in stabilizing folding intermediates, preventing aggregation, and allowing the MHC protein to attain its native structure. Recent experiments have shown that the initial interaction between CRT and a monoglucosylated MHC protein is glycan-driven with glycan-independent interactions representing a second step in the chaperone cycle of CRT. Still, what factors trigger a switch from glycan-dependent to glycan-independent mode of interactions between CRT and its substrate is not well understood. Through computational investigations involving molecular dynamics simulations and structure based molecular docking, we show that ATP-binding serves as a switch for toggling CRT between two distinct modes of interactions. Specifically, the binding of ATP on CRT at the location that is distant from the glycan binding site leads to reduction in the affinity of CRT toward glycans and thus acts as a switch that induces a disengagement of a glycan from CRT, and induces exposure of hydrophobic regions on the surface of the globular domain allowing CRT to act as a chaperone through favoring interactions with the polypeptide component of the MHC. Further, employing community network analysis we have predicted residues that participate in allosteric signaling between ATP and glycan binding site of CRT. Modifying these residues has a large effect on the communication pathways in CRT consistent with experiments and support our model of ATP as a switch for CRT function.