THE THIOL OXIDOREDUCTASE ERP57 IS A COMPONENT OF THE MHC CLASS-I PEPTIDE-LOADING COMPLEX

The proper folding and assembly of major histocompatibility complex (M HC) class I molecules in the endoplasmic reticulum (ER) is an intricat e process involving a number of components. Nascent heavy chains of MH C class I molecules, translocated into the ER membrane, are rapidly gl ycosylated and bind the transmembrane chaperone calnexin [1]. In human s, after dissociation from calnexin, fully oxidized MHC class I heavy chains associate with beta(2)-microglobulin (beta(2)m) and the soluble chaperone calreticulin [2]. This complex interacts with another trans membrane protein, tapasin, which is believed to assist in MHC class I folding as well as in mediating the interaction between assembling MHC class I molecules and the transporter associated with antigen process ing (TAP) [3,4]. The TAP heterodimer (TAP1-TAP2) introduces the final component of the MHC class I molecule by translocating peptides, predo minately generated by the proteasome, from the cytosol into the ER whe re they can bind dimers of beta(2)m and the MHC class I heavy chain [5 ]. Recently, the thiol oxidoreductase ERp57-also known as GRP58, ERp61 , ER60, Q2, HIP-70, and CPT [6] and first misidentified as phospholipa se C-alpha [7]-has been shown to bind in conjunction with calnexin or calreticulin to a number of newly synthesized ER glycoproteins when th eir N-linked glycans are trimmed by glucosidases I and II [8,9]. It wa s speculated that ERp57 is a generic component of the glycan-dependent ER quality control system [10], Here, we show that ERp57 is a compone nt of the MHC class I peptide-loading complex. ERp57 might influence t he folding of MHC class I molecules at a critical step in peptide load ing.