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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alleles
  • Amino Acids
  • Antigen Presentation / immunology*
  • Binding Sites
  • HLA-A2 Antigen / immunology*
  • HLA-A2 Antigen / metabolism
  • Histocompatibility Antigens Class II
  • Humans
  • Peptides / immunology
  • Protein Binding
  • Protozoan Proteins / immunology
  • Protozoan Proteins / metabolism
  • Toxoplasma / immunology


  • Amino Acids
  • HLA-A*02:01 antigen
  • HLA-A2 Antigen
  • Histocompatibility Antigens Class II
  • Peptides
  • Protozoan Proteins

Associated data

  • PDB/5ENW
  • PDB/5F7D
  • PDB/5FA3
  • PDB/5EOT
  • PDB/5F9J
  • PDB/5FDW
  • PDB/5FA4
  • PDB/3MRE