STRUCTURE/BIOLOGY OF SHORT LIVED MHC II LIGAND COMPLEXES

Johns Hopkins University, Baltimore MD

Investigators

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Abstract

DESCRIPTION (Adapted from Investigator's abstract): 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.