期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 20, 页码 5083-5088出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1717277115
关键词
HLA-I-peptide interactions; HLA peptidomics; T cell epitope; HLA-I structures; computational immunology
资金
- Center for Advanced Modeling Science (CADMOS)
- AbbVie [1097737]
- Bayer Pharma AG
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Eshelman Institute for Innovation
- Genome Canada
- Innovative Medicines Initiative (European Federation of Pharmaceutical Industries and Associations) (ULTRA-DD) [115766]
- Janssen
- Merck, Co.
- Novartis Pharma AG
- Ontario Ministry of Economic Development and Innovation
- Pfizer
- Sao Paulo Research Foundation
- Takeda
- Wellcome Trus [092809/Z/10/Z]
- Wellcome Career Development Fellowship [095751/Z/11/Z]
- MRC [MR/N010051/1] Funding Source: UKRI
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.
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