Bidirectional binding of invariant chain peptides to an MHC class II molecule.
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.
Leibniz-Institute for Molecular Pharmacology and Freie Universität Berlin, 13125 Berlin, Germany.
Sebastian
S
Günther
Andreas
A
Schlundt
Jana
J
Sticht
Yvette
Y
Roske
Udo
U
Heinemann
Karl-Heinz
KH
Wiesmüller
Günther
G
Jung
Kirsten
K
Falk
Olaf
O
Rötzschke
Christian
C
Freund
D000944:Antigens, Differentiation, B-Lymphocyte / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018360:Crystallography, X-Ray; D015798:HLA-DR1 Antigen / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000737:chemistry* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D013329:Structure-Activity Relationship
D000944:Antigens, Differentiation, B-Lymphocyte; D015798:HLA-DR1 Antigen; D000949:Histocompatibility Antigens Class II; C045084:invariant chain