The proposed research seeks to extend studies of a kinetic intermediate in the binding of MHC class II molecules to their antigenic peptides. The intermediate complex has low affinity, fast rates of association and dissociation, and its conversion to a stable complex may involve a conformational change. It appears to preserve class II molecules from denaturation at physiological temperatures. Variants of hemagglutinin (HA) peptide 306-318 and mutants of HLA-DR1 have been designed that differ in their binding kinetics and SDS stability and that form only short-lived complexes with HLA-DR1 and certain peptides, respectively. These altered peptides and MHC molecules will be used to gain a better understanding of the physiological significance and structure of short-lived peptide/MHC class II complexes and the mechanisms involved in peptide binding. The """"""""ligand exchange"""""""" model for peptide binding will be tested and the contribution of HLA-DM and segments of the invariant chain (Ii) to peptide exchange will be assessed. In addition, the structure of unstable peptide/DR1 will be determined by X-ray crystallography to investigate the structural basis of unstable binding. The physiological consequences of short-lived complexes will be examined.
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| Narayan, Kedar; Su, Katherine W; Chou, Chih-Ling et al. (2009) HLA-DM mediates peptide exchange by interacting transiently and repeatedly with HLA-DR1. Mol Immunol 46:3157-62 |
| Narayan, Kedar; Perkins, Edward M; Murphy, Gavin E et al. (2009) Staphylococcal enterotoxin A induces small clusters of HLA-DR1 on B cells. PLoS One 4:e6188 |
| Dalai, Sarat K; Mirshahidi, Saied; Morrot, Alexandre et al. (2008) Anergy in memory CD4+ T cells is induced by B cells. J Immunol 181:3221-31 |
| Chou, Chih-Ling; Mirshahidi, Saied; Su, Katherine Wailen et al. (2008) Short peptide sequences mimic HLA-DM functions. Mol Immunol 45:1935-43 |
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