Charge-based interactions through peptide position 4 drive diversity of antigen presentation by human leukocyte antigen class I molecules

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dc.citation.articleNumberpgac124
dc.citation.issueNumber3
dc.citation.journalTitlePNAS Nexus
dc.citation.volumeNumber1
dc.contributor.authorJackson, Kyle R
dc.contributor.authorAntunes, Dinler A
dc.contributor.authorTalukder, Amjad H
dc.contributor.authorMaleki, Ariana R
dc.contributor.authorAmagai, Kano
dc.contributor.authorSalmon, Avery
dc.contributor.authorKatailiha, Arjun S
dc.contributor.authorChiu, Yulun
dc.contributor.authorFasoulis, Romanos
dc.contributor.authorRigo, Maurício Menegatti
dc.contributor.authorAbella, Jayvee R
dc.contributor.authorMelendez, Brenda D
dc.contributor.authorLi, Fenge
dc.contributor.authorSun, Yimo
dc.contributor.authorSonnemann, Heather M
dc.contributor.authorBelousov, Vladislav
dc.contributor.authorFrenkel, Felix
dc.contributor.authorJustesen, Sune
dc.contributor.authorMakaju, Aman
dc.contributor.authorLiu, Yang
dc.contributor.authorHorn, David
dc.contributor.authorLopez-Ferrer, Daniel
dc.contributor.authorHuhmer, Andreas F
dc.contributor.authorHwu, Patrick
dc.contributor.authorRoszik, Jason
dc.contributor.authorHawke, David
dc.contributor.authorKavraki, Lydia E
dc.contributor.authorLizée, Gregory
dc.date.accessioned2024-05-03T15:51:13Z
dc.date.available2024-05-03T15:51:13Z
dc.date.issued2022
dc.description.abstractHuman leukocyte antigen class I (HLA-I) molecules bind and present peptides at the cell surface to facilitate the induction of appropriate CD8+ T cell-mediated immune responses to pathogen- and self-derived proteins. The HLA-I peptide-binding cleft contains dominant anchor sites in the B and F pockets that interact primarily with amino acids at peptide position 2 and the C-terminus, respectively. Nonpocket peptide–HLA interactions also contribute to peptide binding and stability, but these secondary interactions are thought to be unique to individual HLA allotypes or to specific peptide antigens. Here, we show that two positively charged residues located near the top of peptide-binding cleft facilitate interactions with negatively charged residues at position 4 of presented peptides, which occur at elevated frequencies across most HLA-I allotypes. Loss of these interactions was shown to impair HLA-I/peptide binding and complex stability, as demonstrated by both in vitro and in silico experiments. Furthermore, mutation of these Arginine-65 (R65) and/or Lysine-66 (K66) residues in HLA-A*02:01 and A*24:02 significantly reduced HLA-I cell surface expression while also reducing the diversity of the presented peptide repertoire by up to 5-fold. The impact of the R65 mutation demonstrates that nonpocket HLA-I/peptide interactions can constitute anchor motifs that exert an unexpectedly broad influence on HLA-I-mediated antigen presentation. These findings provide fundamental insights into peptide antigen binding that could broadly inform epitope discovery in the context of viral vaccine development and cancer immunotherapy.
dc.identifier.citationJackson, K. R., Antunes, D. A., Talukder, A. H., Maleki, A. R., Amagai, K., Salmon, A., Katailiha, A. S., Chiu, Y., Fasoulis, R., Rigo, M. M., Abella, J. R., Melendez, B. D., Li, F., Sun, Y., Sonnemann, H. M., Belousov, V., Frenkel, F., Justesen, S., Makaju, A., … Lizée, G. (2022). Charge-based interactions through peptide position 4 drive diversity of antigen presentation by human leukocyte antigen class I molecules. PNAS Nexus, 1(3), pgac124. https://doi.org/10.1093/pnasnexus/pgac124
dc.identifier.digitalpgac124
dc.identifier.doihttps://doi.org/10.1093/pnasnexus/pgac124
dc.identifier.urihttps://hdl.handle.net/1911/115575
dc.language.isoeng
dc.publisherOxford University Press
dc.rightsExcept where otherwise noted, this work is licensed under a Creative Commons Attribution (CC BY) license. Permission to reuse, publish, or reproduce the work beyond the terms of the license or beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.titleCharge-based interactions through peptide position 4 drive diversity of antigen presentation by human leukocyte antigen class I molecules
dc.typeJournal article
dc.type.dcmiText
dc.type.publicationpublisher version
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