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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.

Author information

1
From the Division for Cell Biology and.
2
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037.
3
Instituto de Investigaciones Biotecnológicas, Universidad Nacional de San Martín, CP1650 San Martín, Argentina.
4
Center for Biological Sequence Analysis, Department of Bio and Health Informatics, The Technical University of Denmark, 2800 Lyngby, Denmark.
5
Department of Microbiology and Immunology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104.
6
Pure MHC LLC, Austin, Texas 78229, and.
7
From the Division for Cell Biology and dzajonc@lji.org.
8
Department of Internal Medicine, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium.

Abstract

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.

KEYWORDS:

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

PMID:
28179428
PMCID:
PMC5392673
DOI:
10.1074/jbc.M117.776542
[Indexed for MEDLINE]
Free PMC Article

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