Deciphering HLA-I motifs across HLA peptidomes improves neo-antigen predictions and identifies allostery regulating HLA specificity.

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State: Public
Version: Final published version
Serval ID
serval:BIB_0F969601F848
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Deciphering HLA-I motifs across HLA peptidomes improves neo-antigen predictions and identifies allostery regulating HLA specificity.
Journal
PLoS Computational Biology
Author(s)
Bassani-Sternberg M., Chong C., Guillaume P., Solleder M., Pak H., Gannon P.O., Kandalaft L.E., Coukos G., Gfeller D.
ISSN
1553-7358 (Electronic)
ISSN-L
1553-734X
Publication state
Published
Issued date
2017
Peer-reviewed
Oui
Volume
13
Number
8
Pages
e1005725
Language
english
Abstract
The precise identification of Human Leukocyte Antigen class I (HLA-I) binding motifs plays a central role in our ability to understand and predict (neo-)antigen presentation in infectious diseases and cancer. Here, by exploiting co-occurrence of HLA-I alleles across ten newly generated as well as forty public HLA peptidomics datasets comprising more than 115,000 unique peptides, we show that we can rapidly and accurately identify many HLA-I binding motifs and map them to their corresponding alleles without any a priori knowledge of HLA-I binding specificity. Our approach recapitulates and refines known motifs for 43 of the most frequent alleles, uncovers new motifs for 9 alleles that up to now had less than five known ligands and provides a scalable framework to incorporate additional HLA peptidomics studies in the future. The refined motifs improve neo-antigen and cancer testis antigen predictions, indicating that unbiased HLA peptidomics data are ideal for in silico predictions of neo-antigens from tumor exome sequencing data. The new motifs further reveal distant modulation of the binding specificity at P2 for some HLA-I alleles by residues in the HLA-I binding site but outside of the B-pocket and we unravel the underlying mechanisms by protein structure analysis, mutagenesis and in vitro binding assays.

Keywords
Amino Acid Motifs/genetics, Binding Sites/genetics, Histocompatibility Antigens Class I/chemistry, Histocompatibility Antigens Class I/genetics, Histocompatibility Antigens Class I/metabolism, Humans, Peptides/analysis, Peptides/chemistry, Peptides/genetics, Peptides/metabolism, Protein Binding/genetics, Proteome/chemistry, Proteome/genetics, Proteome/metabolism, Proteomics/methods
Pubmed
Web of science
Open Access
Yes
Create date
25/09/2017 17:25
Last modification date
20/08/2019 12:36
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