Unconventional Peptide Presentation by Major Histocompatibility Complex (MHC) Class I Allele HLA-A*02:01: BREAKING CONFINEMENT.
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 fromToxoplasma gondiibound 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.
From the Division for Cell Biology and.
Soumya G
SG
Remesh
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.
Massimo
M
Andreatta
From the Division for Cell Biology and.
Ge
G
Ying
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037.
Thomas
T
Kaever
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.
Morten
M
Nielsen
Department of Microbiology and Immunology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104.|Pure MHC LLC, Austin, Texas 78229, and.
Curtis
C
McMurtrey
Department of Microbiology and Immunology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma 73104.|Pure MHC LLC, Austin, Texas 78229, and.
William
W
Hildebrand
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037.
Bjoern
B
Peters
From the Division for Cell Biology and dzajonc@lji.org.|Department of Internal Medicine, Faculty of Medicine and Health Sciences, Ghent University, 9000 Ghent, Belgium.
Dirk M
DM
Zajonc
D000483:Alleles; D000596:Amino Acids; D017951:Antigen Presentation / Q000276:immunology*; D001665:Binding Sites; D015789:HLA-A2 Antigen / Q000276:immunology* / Q000378:metabolism; D000949:Histocompatibility Antigens Class II; D006801:Humans; D010455:Peptides / Q000276:immunology; D011485:Protein Binding; D015800:Protozoan Proteins / Q000276:immunology / Q000378:metabolism; D014122:Toxoplasma / Q000276:immunology
D000596:Amino Acids; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D000949:Histocompatibility Antigens Class II; D010455:Peptides; D015800:Protozoan Proteins
T-cell receptor (TCR); Toxoplasma gondii; antigen presentation; major histocompatibility complex (MHC); natural killer cells (NK cells); peptide interaction; protein crystallization; protein structure