Bidirectional binding of invariant chain peptides to an MHC class II molecule
Edited by Emil R. Unanue, Washington University, St. Louis, MO, and approved November 2, 2010 (received for review September 30, 2010)
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.
Data Availability
Data deposition: The structures reported in this paper have been deposited in the Protein Data Bank database (accession nos. 3PDO, 3PGC, and 3PGD).
Acknowledgments
We thank Michael Beyermann for standard peptide synthesis; Peter Schmieder for the setup of certain NMR pulse sequences; Ronald Kühne for helpful discussions; and Miriam-Rose Ash for critically reading the manuscript. C.F. was supported by grants from the Bundesministerium für Bildung und Forschung (01 EZ 1010B) and from the Deutsche Forschungsgemeinschaft (SFB765).
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Data Availability
Data deposition: The structures reported in this paper have been deposited in the Protein Data Bank database (accession nos. 3PDO, 3PGC, and 3PGD).
Submission history
Published online: November 29, 2010
Published in issue: December 21, 2010
Keywords
Acknowledgments
We thank Michael Beyermann for standard peptide synthesis; Peter Schmieder for the setup of certain NMR pulse sequences; Ronald Kühne for helpful discussions; and Miriam-Rose Ash for critically reading the manuscript. C.F. was supported by grants from the Bundesministerium für Bildung und Forschung (01 EZ 1010B) and from the Deutsche Forschungsgemeinschaft (SFB765).
Notes
*This Direct Submission article had a prearranged editor.
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The authors declare no conflict of interest.
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Cite this article
Bidirectional binding of invariant chain peptides to an MHC class II molecule, Proc. Natl. Acad. Sci. U.S.A.
107 (51) 22219-22224,
https://doi.org/10.1073/pnas.1014708107
(2010).
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