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

Soumya G Remesh,Massimo Andreatta,Ge Ying,Thomas Kaever,Morten Nielsen,Curtis Mcmurtrey,William Hildebrand,Bjoern Peters,Dirk M Zajonc

doi:10.1074/jbc.m117.776542

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.

Highlights

BREAKING CONFINEMENT*Peptide-induced Opening of the F Pocket of major histocompatibility complex (MHC) Class I groove, respectively, whereas the middle portion of these oversized peptides either “bulge out” or “zigzag” in the binding groove to be accommodated [18, 19]
Peptide presentation by major histocompatibility complex (MHC) class I molecules regulates which fragments of a pathogen or cancer antigen are displayed to cytotoxic T cells for immune recognition
T. gondii can interfere with CD4 T cell responses by down-regulating MHC II expression in IFN-␥-activated macrophages, immunization with T. gondii MHC II peptide ligands can elicit a potent CD4 T cell response that can lower parasite burden in the brain [6, 7]

Summary

BREAKING CONFINEMENT*

Peptide-induced Opening of the F Pocket of MHC Class I groove, respectively, whereas the middle portion of these oversized peptides either “bulge out” or “zigzag” in the binding groove to be accommodated [18, 19] In contrast to these “bulged” peptides, we recently identified longer T. gondii peptides eluted from HLA-A*02:01 molecules that had a conserved N-terminal start but differed in their residue composition at the C terminus [20]. We showed through crystallographic studies that in the HLA-A*02:01 complex with one 12-mer peptide residue Tyr-84 of the MHC heavy chain swung out and opened the F pocket, allowing the C-terminal amino acid of the peptide to protrude into the solvent, whereas the nested 11-mer N-terminal core peptide bound in a conventional zigzag orientation tucked with both peptide ends inside the peptide binding groove. We suggest that these unconventional modes of binding will help better understand targets of MHC class I-restricted epitope recognition

Results

Water molecules

Discussion

Experimental Procedures