The Kinetic Basis of Peptide Exchange Catalysis by HLA-DM

The mechanism by which the peptide exchange factor HLA-DM catalyzes peptide loading onto structurally homologous class II MHC proteins is an outstanding problem in antigen presentation. The peptide-loading reaction of class II MHC proteins is complex and includes conformational changes in both empty...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2001-10, Vol.98 (22), p.12450-12455
Main Authors: Zarutskie, Jennifer A., Busch, Robert, Zavala-Ruiz, Zarixia, Rushe, Mia, Mellins, Elizabeth D., Stern, Lawrence J.
Format: Article
Language:English
Subjects:
Antigens, Differentiation, B-Lymphocyte - metabolism
Biochemistry
Biological Sciences
Catalysis
Chemical bonds
Chromatography
Circles
Fluorescence
Hemagglutinin Glycoproteins, Influenza Virus - metabolism
histocompatibility antigen HLA
Histocompatibility Antigens Class II - metabolism
HLA-D Antigens - pharmacology
HLA-DR1 Antigen - metabolism
Immunity
Kinetics
Molecules
Peptides
Protein Conformation
Protein Folding
Proteins
Reactants
Titration
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Summary:The mechanism by which the peptide exchange factor HLA-DM catalyzes peptide loading onto structurally homologous class II MHC proteins is an outstanding problem in antigen presentation. The peptide-loading reaction of class II MHC proteins is complex and includes conformational changes in both empty and peptide-bound forms in addition to a bimolecular binding step. By using a fluorescence energy transfer assay to follow the kinetics of peptide binding to the human class II MHC protein HLA-DR1, we find that HLA-DM catalyzes peptide exchange by facilitating a conformational change in the peptide-bound complex, and not by promoting the bimolecular MHC-peptide reaction or the conversion between peptide-receptive and -averse forms of the empty protein. Thus, HLA-DM serves essentially as a protein-folding or conformational catalyst.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.211439398