Breaking confinement: unconventional peptide presentation by major histocompatibility (MHC) class I allele HLA-A*02:01

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

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Abstract

Peptide antigen-presentation by Major Histocompatibility Class (MHC) I proteins initiates CD8+ T cell mediated immunity against pathogens and cancers. MHC I molecules typically bind peptides with nine amino acids in length with both ends tucked inside the major A and F binding pocket. 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 zig-zag 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. While positively charged amino acid result in the Tyr84 swing, amino acids that are negatively charged induce a not previously described Lys146 lift. Further, 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.
Original languageEnglish
Article numberjbc.M117.776542
JournalJournal of Biological Chemistry
Volume292
Issue number13
Pages (from-to)5262-5270
ISSN0021-9258
DOIs
Publication statusPublished - 2017

Keywords

  • 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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