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J Biol Chem. 2017 Mar 31;292(13):5262-5270. doi: 10.1074/jbc.M117.776542. Epub 2017 Feb 8.

Unconventional Peptide Presentation by Major Histocompatibility Complex (MHC) Class I Allele HLA-A*02:01: BREAKING CONFINEMENT.

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From the Division for Cell Biology and.
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037.
Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín, CP1650 San Martín, Argentina.
Center for Biological Sequence Analysis, Department of Bio and Health Informatics, The Technical University of Denmark, 2800 Lyngby, Denmark.
Department of Microbiology and Immunology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104.
Pure MHC LLC, Austin, Texas 78229, and.
From the Division for Cell Biology and
Department of Internal Medicine, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium.


Peptide antigen presentation by major histocompatibility complex (MHC) class I proteins initiates CD8+ T cell-mediated immunity against pathogens and cancers. MHC I molecules typically bind peptides with 9 amino acids in length with both ends tucked inside the major A and F binding pockets. It has been known for a while that longer peptides can also bind by either bulging out of the groove in the middle of the peptide or by binding in a zigzag fashion inside the groove. In a recent study, we identified an alternative binding conformation of naturally occurring peptides from Toxoplasma gondii bound by HLA-A*02:01. These peptides were extended at the C terminus (PΩ) and contained charged amino acids not more than 3 residues after the anchor amino acid at PΩ, which enabled them to open the F pocket and expose their C-terminal extension into the solvent. Here, we show that the mechanism of F pocket opening is dictated by the charge of the first charged amino acid found within the extension. Although positively charged amino acids result in the Tyr-84 swing, amino acids that are negatively charged induce a not previously described Lys-146 lift. Furthermore, we demonstrate that the peptides with alternative binding modes have properties that fit very poorly to the conventional MHC class I pathway and suggest they are presented via alternative means, potentially including cross-presentation via the MHC class II pathway.


T-cell receptor (TCR); Toxoplasma gondii; antigen presentation; major histocompatibility complex (MHC); natural killer cells (NK cells); peptide interaction; protein crystallization; protein structure

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