Bidirectional binding of invariant chain peptides to an MHC class II molecule

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 51; pp. 22219 - 22224
• Main Authors: Günther, Sebastian, Schlundt, Andreas, Sticht, Jana, Roske, Yvette, Heinemann, Udo, Wiesmüller, Karl-Heinz, Jung, Günther, Falk, Kirsten, Rötzschke, Olaf, Freund, Christian, Unanue, Emil R.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 21.12.2010; National Acad Sciences
• Subjects: adaptive immunity; Antigen presenting cells; Antigens; Antigens, Differentiation, B-Lymphocyte - chemistry; Antigens, Differentiation, B-Lymphocyte - genetics; Antigens, Differentiation, B-Lymphocyte - immunology; Antigens, Differentiation, B-Lymphocyte - metabolism; Binding sites; Biochemistry; Biological Sciences; Catalysts; Chemical equilibrium; Class II-associated invariant chain peptides; Crystal structure; Crystallography; Crystallography, X-Ray; Histocompatibility antigen HLA; Histocompatibility Antigens Class II - chemistry; Histocompatibility Antigens Class II - genetics; Histocompatibility Antigens Class II - immunology; Histocompatibility Antigens Class II - metabolism; HLA-DR1 Antigen - chemistry; HLA-DR1 Antigen - genetics; HLA-DR1 Antigen - immunology; HLA-DR1 Antigen - metabolism; Humans; Hydrogen bonding; Hydrogen bonds; Immunity; Immunity (cell-mediated); Invariant chain; Inversion; Lymphocytes T; Magnetic resonance spectroscopy; Major histocompatibility complex; Major histocompatibility complex genes; Molecules; nuclear magnetic resonance spectroscopy; Nuclear Magnetic Resonance, Biomolecular; Peptides; Protein Binding; Protein refolding; Protein Structure, Quaternary; Proteins; Spectrum analysis; Structure-Activity Relationship; T cell receptors; T lymphocytes; X-ray crystallography; X-ray diffraction
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1014708107

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.