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

DOI: 10.1073/pnas.1717277115

Authors: Philippe Guillaume (Ludwig Institute for Cancer Research, University of Lausanne) , Sarah Picaud (Structural Genomics Consortium, University of Oxford) , Petra Baumgaertner (Ludwig Institute for Cancer Research, University of Lausanne) , Nicole Montandon (Ludwig Institute for Cancer Research, University of Lausanne) , Julien Schmidt (Ludwig Institute for Cancer Research, University of Lausanne) , Daniel E. Speiser (Ludwig Institute for Cancer Research, University of Lausanne) , George Coukos (Ludwig Institute for Cancer Research, University of Lausanne) , Michal Bassani-Sternberg (Ludwig Institute for Cancer Research, University of Lausanne) , Panagis Filippakopoulos (Structural Genomics Consortium, University of Oxford) , David Gfeller (Ludwig Institute for Cancer Research, University of Lausanne)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Proceedings Of The National Academy Of Sciences , VOL 115 , PAGES 5083 - 5088

State: Published (Approved)
Published: May 2018
Diamond Proposal Number(s): 15433

Abstract: 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.

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

Diamond Keywords: Immunotherapy

Subject Areas: Biology and Bio-materials


Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 31/05/2018 11:23

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)