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

Guillaume, P.; Picaud, S.; Baumgaertner, P.; Montandon, N.; Schmidt, J.; Speiser, D. E.; Coukos, G.; Bassani-Sternberg, M.; Fillipakopoulos, P.; Gfeller, D.

doi:10.1101/213264

bioRxiv · 10.1101/213264

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

Guillaume, P.·Picaud, S.·Baumgaertner, P.·Montandon, N.·Schmidt, J.·Speiser, D. E.·Coukos, G.·Bassani-Sternberg, M.·Fillipakopoulos, P.·Gfeller, D.

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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 non-canonical binding modes we collected in-depth and accurate HLA peptidomics datasets covering 54 HLA-I alleles and developed novel 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 new C-terminal extension motifs identifies many putative epitopes and we demonstrate direct recognition by human CD8+ T cells of a C-terminally extended epitope from cytomegalovirus.

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Guillaume, P., Picaud, S., Baumgaertner, P., Montandon, N., Schmidt, J., Speiser, D. E., Coukos, G., Bassani-Sternberg, M., Fillipakopoulos, P., Gfeller, D.. 2017-11-02. The C-terminal extension landscape of naturally presented HLA-I ligands. https://doi.org/10.1101/213264

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