The C-terminal extension landscape of naturally presented HLA-I ligands

Proc Natl Acad Sci U S A. 2018 May 15;115(20):5083-5088. doi: 10.1073/pnas.1717277115. Epub 2018 Apr 30.


HLA-I molecules play a central role in antigen presentation. They typically bind 9- to 12-mer peptides, and their canonical binding mode involves anchor residues at the second and last positions of their ligands. To investigate potential noncanonical binding modes, we collected in-depth and accurate HLA peptidomics datasets covering 54 HLA-I alleles and developed algorithms to analyze these data. Our results reveal frequent (442 unique peptides) and statistically significant C-terminal extensions for at least eight alleles, including the common HLA-A03:01, HLA-A31:01, and HLA-A68:01. High resolution crystal structure of HLA-A68:01 with such a ligand uncovers structural changes taking place to accommodate C-terminal extensions and helps unraveling sequence and structural properties predictive of the presence of these extensions. Scanning viral proteomes with the C-terminal extension motifs identifies many putative epitopes and we demonstrate direct recognition by human CD8+ T cells of a 10-mer epitope from cytomegalovirus predicted to follow the C-terminal extension binding mode.

Keywords: HLA peptidomics; HLA-I structures; HLA-I–peptide interactions; T cell epitope; computational immunology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Amino Acid Sequence
  • Antigen Presentation / immunology*
  • Crystallography, X-Ray
  • Epitopes, T-Lymphocyte / immunology*
  • HLA Antigens / immunology*
  • Humans
  • Ligands
  • Peptide Fragments / immunology*
  • Protein Binding
  • T-Lymphocytes / immunology*


  • Epitopes, T-Lymphocyte
  • HLA Antigens
  • Ligands
  • Peptide Fragments

Associated data

  • PDB/6EI2