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

Autor: Jackson KR; University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA., Antunes DA; Department of Biology and Biochemistry, University of Houston, Houston, TX, USA., Talukder AH; Department of Melanoma, UT MD Anderson Cancer Center, Houston, TX, USA., Maleki AR; Department of Melanoma, UT MD Anderson Cancer Center, Houston, TX, USA., Amagai K; Department of Melanoma, UT MD Anderson Cancer Center, Houston, TX, USA., Salmon A; University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA., Katailiha AS; Department of Melanoma, UT MD Anderson Cancer Center, Houston, TX, USA., Chiu Y; Department of Melanoma, UT MD Anderson Cancer Center, Houston, TX, USA., Fasoulis R; Department of Computer Science, Rice University, Houston, TX, USA., Rigo MM; Department of Computer Science, Rice University, Houston, TX, USA., Abella JR; Department of Computer Science, Rice University, Houston, TX, USA., Melendez BD; University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA., Li F; Department of Melanoma, UT MD Anderson Cancer Center, Houston, TX, USA., Sun Y; University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA., Sonnemann HM; University of Texas MD Anderson Cancer Center, UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA., Belousov V; BostonGene Corporation, Waltham, MA, USA., Frenkel F; BostonGene Corporation, Waltham, MA, USA., Justesen S; Immunitrack Aps, Copenhagen, Denmark., Makaju A; ThermoFisher Scientific, San Jose, CA, USA., Liu Y; ThermoFisher Scientific, San Jose, CA, USA., Horn D; ThermoFisher Scientific, San Jose, CA, USA., Lopez-Ferrer D; ThermoFisher Scientific, San Jose, CA, USA., Huhmer AF; ThermoFisher Scientific, San Jose, CA, USA., Hwu P; Department of Melanoma, UT MD Anderson Cancer Center, Houston, TX, USA., Roszik J; Department of Melanoma, UT MD Anderson Cancer Center, Houston, TX, USA., Hawke D; Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX, USA., Kavraki LE; Department of Computer Science, Rice University, Houston, TX, USA., Lizée G; Department of Melanoma, UT MD Anderson Cancer Center, Houston, TX, USA.
Jazyk: angličtina
Zdroj: PNAS nexus [PNAS Nexus] 2022 Jul 27; Vol. 1 (3), pp. pgac124. Date of Electronic Publication: 2022 Jul 27 (Print Publication: 2022).
DOI: 10.1093/pnasnexus/pgac124
Abstrakt: Human 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.
(© The Author(s) 2022. Published by Oxford University Press on behalf of the National Academy of Sciences.)
Databáze: MEDLINE
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