학술논문
Charge-based interactions through peptide position 4 drive diversity of antigen presentation by human leukocyte antigen class I molecules
Research Report
Research Report
Document Type
Report
Author
Jackson, Kyle R.; Antunes, Dinler A.; Talukder, Amjad H.; Maleki, Ariana R.; Amagai, Kano; Salmon, Avery; Katailiha, Arjun S.; Chiu, Yulun; Fasoulis, Romanos; Rigo, Mauricio Menegatti; Abella, Jayvee R.; Melendez, Brenda D.; Li, Fenge; Sun, Yimo; Sonnemann, Heather M.; Belousov, Vladislav; Frenkel, Felix; Justesen, Sune; Makaju, Aman; Liu, Yang; Horn, David; Lopez-Ferrer, Daniel; Huhmer, Andreas F.; Hwu, Patrick; Roszik, Jason; Hawke, David; Kavraki, Lydia E.; Lizee, Gregory
Source
PNAS Nexus. July 2022, Vol. 1 Issue 3
Subject
Language
English
ISSN
2752-6542
Abstract
Background Major histocompatibility complex class I (MHC-I) molecules are expressed at the surface of nearly all nucleated vertebrate cells, where they each present a diverse array of peptides of 8 [...]
Human leukocyte antigen class I (HLA-I) molecules bind and present peptides at the cell surface to facilitate the induction of appropriate [CD8.sup.+] 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. Keywords: peptide antigen presentation, human leukocyte antigen (HLA), mass spectrometry, computational modeling, molecular dynamics
Human leukocyte antigen class I (HLA-I) molecules bind and present peptides at the cell surface to facilitate the induction of appropriate [CD8.sup.+] 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. Keywords: peptide antigen presentation, human leukocyte antigen (HLA), mass spectrometry, computational modeling, molecular dynamics