Loading of peptides into class I molecules occurs in the ER and this process is now known to involve the interaction of several ER proteins, including TAP, gp48 and calreticulin. This grant proposal will define the separate roles of each of these molecules in the ER retention of class I prior to peptide loading and their role in the facilitation of class I assembly.
Three specific aims are proposed: 1) determine whether TAP, calreticulin and/or gp48 is responsible for peptide-induced release of class I from ER retention; 2) define specific interactions between members of the TAP/calreticulin/gp48 complex using mutant class I chains; and 3) define the role of calreticulin using genetic approaches. In this final aim we will genetically disrupt the calreticulin gene to critically assess the role of this known chaperone in class I folding and peptide loading. Basic information obtained from these studies will be fundamental to our understanding of class I antigen presentation and may help in the future design of rational approaches for clinical intervention.
| Yu, Y Y Lawrence; Harris, Michael R; Lybarger, Lonnie et al. (2002) Physical association of the K3 protein of gamma-2 herpesvirus 68 with major histocompatibility complex class I molecules with impaired peptide and beta(2)-microglobulin assembly. J Virol 76:2796-803 |
| Harris, M R; Lybarger, L; Yu, Y Y et al. (2001) Association of ERp57 with mouse MHC class I molecules is tapasin dependent and mimics that of calreticulin and not calnexin. J Immunol 166:6686-92 |
| Harris, M R; Lybarger, L; Myers, N B et al. (2001) Interactions of HLA-B27 with the peptide loading complex as revealed by heavy chain mutations. Int Immunol 13:1275-82 |
| Yu, Y Y; Myers, N B; Hilbert, C M et al. (1999) Definition and transfer of a serological epitope specific for peptide-empty forms of MHC class I. Int Immunol 11:1897-906 |
