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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM053549-01A2
Application #
2632915
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1998-05-01
Project End
2003-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Pathology
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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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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