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


  • S. Guenther
  • A. Schlundt
  • J. Sticht
  • Y. Roske
  • U. Heinemann
  • K.H. Wiesmueller
  • G. Jung
  • K. Falk
  • O. Roetzschke
  • C. Freund


  • Proceedings of the National Academy of Sciences of the United States of America


  • Proc Natl Acad Sci U S A 107 (51): 22219-22224


  • 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.