A hairpin turn in a class II MHC-bound peptide orients residues outside the binding groove for T cell recognition.
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.
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Zarixia
Z
Zavala-Ruiz
Iwona
I
Strug
Bruce D
BD
Walker
Philip J
PJ
Norris
Lawrence J
LJ
Stern
D000595:Amino Acid Sequence; D017951:Antigen Presentation; D001665:Binding Sites; D003460:Crystallization; D016655:HIV Core Protein p24 / Q000737:chemistry*; D015798:HLA-DR1 Antigen / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry*; D011487:Protein Conformation; D013601:T-Lymphocytes / Q000276:immunology*
D016655:HIV Core Protein p24; D015798:HLA-DR1 Antigen; D010446:Peptide Fragments