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.articleNumberpgac124en_US
dc.citation.issueNumber3en_US
dc.citation.journalTitlePNAS Nexusen_US
dc.citation.volumeNumber1en_US
dc.contributor.authorJackson, Kyle Ren_US
dc.contributor.authorAntunes, Dinler Aen_US
dc.contributor.authorTalukder, Amjad Hen_US
dc.contributor.authorMaleki, Ariana Ren_US
dc.contributor.authorAmagai, Kanoen_US
dc.contributor.authorSalmon, Averyen_US
dc.contributor.authorKatailiha, Arjun Sen_US
dc.contributor.authorChiu, Yulunen_US
dc.contributor.authorFasoulis, Romanosen_US
dc.contributor.authorRigo, Maurício Menegattien_US
dc.contributor.authorAbella, Jayvee Ren_US
dc.contributor.authorMelendez, Brenda Den_US
dc.contributor.authorLi, Fengeen_US
dc.contributor.authorSun, Yimoen_US
dc.contributor.authorSonnemann, Heather Men_US
dc.contributor.authorBelousov, Vladislaven_US
dc.contributor.authorFrenkel, Felixen_US
dc.contributor.authorJustesen, Suneen_US
dc.contributor.authorMakaju, Amanen_US
dc.contributor.authorLiu, Yangen_US
dc.contributor.authorHorn, Daviden_US
dc.contributor.authorLopez-Ferrer, Danielen_US
dc.contributor.authorHuhmer, Andreas Fen_US
dc.contributor.authorHwu, Patricken_US
dc.contributor.authorRoszik, Jasonen_US
dc.contributor.authorHawke, Daviden_US
dc.contributor.authorKavraki, Lydia Een_US
dc.contributor.authorLizée, Gregoryen_US
dc.date.accessioned2024-05-03T15:51:13Zen_US
dc.date.available2024-05-03T15:51:13Zen_US
dc.date.issued2022en_US
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.en_US
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/pgac124en_US
dc.identifier.digitalpgac124en_US
dc.identifier.doihttps://doi.org/10.1093/pnasnexus/pgac124en_US
dc.identifier.urihttps://hdl.handle.net/1911/115575en_US
dc.language.isoengen_US
dc.publisherOxford University Pressen_US
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.en_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.titleCharge-based interactions through peptide position 4 drive diversity of antigen presentation by human leukocyte antigen class I moleculesen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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