Abstract
T-cell recognition of peptides bound to MHC class II (MHCII) molecules is a central event in cell-mediated adaptive immunity. The current paradigm holds that prebound class II-associated invariant chain peptides (CLIP) and all subsequent antigens maintain a canonical orientation in the MHCII binding groove. Here we provide evidence for MHCII-bound CLIP inversion. NMR spectroscopy demonstrates that the interconversion from the canonical to the inverse alignment is a dynamic process, and X-ray crystallography shows that conserved MHC residues form a hydrogen bond network with the peptide backbone in both orientations. The natural catalyst HLA-DM accelerates peptide reorientation and the exchange of either canonically or inversely bound CLIP against antigenic peptide. Thus, noncanonical MHC-CLIP displays the hallmarks of a structurally and functionally intact antigen-presenting complex.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antigens, Differentiation, B-Lymphocyte / chemistry*
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Antigens, Differentiation, B-Lymphocyte / genetics
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Antigens, Differentiation, B-Lymphocyte / immunology
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Antigens, Differentiation, B-Lymphocyte / metabolism
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Crystallography, X-Ray
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HLA-DR1 Antigen / chemistry*
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HLA-DR1 Antigen / genetics
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HLA-DR1 Antigen / immunology
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HLA-DR1 Antigen / metabolism
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Histocompatibility Antigens Class II / chemistry*
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Histocompatibility Antigens Class II / genetics
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Histocompatibility Antigens Class II / immunology
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Histocompatibility Antigens Class II / metabolism
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Humans
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Nuclear Magnetic Resonance, Biomolecular
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Protein Binding
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Protein Structure, Quaternary
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Structure-Activity Relationship
Substances
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Antigens, Differentiation, B-Lymphocyte
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HLA-DR1 Antigen
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Histocompatibility Antigens Class II
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invariant chain
Associated data
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PDB/3PDO
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PDB/3PGC
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PDB/3PGD