A hairpin turn in a class II MHC-bound peptide orients residues outside the binding groove for T cell recognition

Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13279-84. doi: 10.1073/pnas.0403371101. Epub 2004 Aug 26.

Abstract

T cells generally recognize peptide antigens bound to MHC proteins through contacts with residues found within or immediately flanking the seven- to nine-residue sequence accommodated in the MHC peptide-binding groove. However, some T cells require peptide residues outside this region for activation, the structural basis for which is unknown. Here, we have investigated a HIV Gag-specific T cell clone that requires an unusually long peptide antigen for activation. The crystal structure of a minimally antigenic 16-mer bound to HLA-DR1 shows that the peptide C-terminal region bends sharply into a hairpin turn as it exits the binding site, orienting peptide residues outside the MHC-binding region in position to interact with a T cell receptor. Peptide truncation and substitution studies show that both the hairpin turn and the extreme C-terminal residues are required for T cell activation. These results demonstrate a previously unrecognized mode of MHC-peptide-T cell receptor interaction.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Antigen Presentation
  • Binding Sites
  • Crystallization
  • HIV Core Protein p24 / chemistry*
  • HLA-DR1 Antigen / metabolism*
  • Humans
  • Lymphocyte Activation*
  • Molecular Sequence Data
  • Peptide Fragments / chemistry*
  • Protein Conformation
  • T-Lymphocytes / immunology*

Substances

  • HIV Core Protein p24
  • HLA-DR1 Antigen
  • Peptide Fragments

Associated data

  • PDB/1SJE
  • PDB/1SJH