Browsing by Author "Fasoulis, Romanos"
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Item Charge-based interactions through peptide position 4 drive diversity of antigen presentation by human leukocyte antigen class I molecules(Oxford University Press, 2022) Jackson, Kyle R; Antunes, Dinler A; Talukder, Amjad H; Maleki, Ariana R; Amagai, Kano; Salmon, Avery; Katailiha, Arjun S; Chiu, Yulun; Fasoulis, Romanos; Rigo, Maurício 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; Lizée, GregoryHuman 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.Item SARS-Arena: Sequence and Structure-Guided Selection of Conserved Peptides from SARS-related Coronaviruses for Novel Vaccine Development(Frontiers Media S.A., 2022) Rigo, Mauricio Menegatti; Fasoulis, Romanos; Conev, Anja; Hall-Swan, Sarah; Antunes, Dinler Amaral; Kavraki, Lydia E.; Kavraki LabThe pandemic caused by the SARS-CoV-2 virus, the agent responsible for the COVID-19 disease, has affected millions of people worldwide. There is constant search for new therapies to either prevent or mitigate the disease. Fortunately, we have observed the successful development of multiple vaccines. Most of them are focused on one viral envelope protein, the spike protein. However, such focused approaches may contribute for the rise of new variants, fueled by the constant selection pressure on envelope proteins, and the widespread dispersion of coronaviruses in nature. Therefore, it is important to examine other proteins, preferentially those that are less susceptible to selection pressure, such as the nucleocapsid (N) protein. Even though the N protein is less accessible to humoral response, peptides from its conserved regions can be presented by class I Human Leukocyte Antigen (HLA) molecules, eliciting an immune response mediated by T-cells. Given the increased number of protein sequences deposited in biological databases daily and the N protein conservation among viral strains, computational methods can be leveraged to discover potential new targets for SARS-CoV-2 and SARS-CoV-related viruses. Here we developed SARS-Arena, a user-friendly computational pipeline that can be used by practitioners of different levels of expertise for novel vaccine development. SARS-Arena combines sequence-based methods and structure-based analyses to (i) perform multiple sequence alignment (MSA) of SARS-CoV-related N protein sequences, (ii) recover candidate peptides of different lengths from conserved protein regions, and (iii) model the 3D structure of the conserved peptides in the context of different HLAs. We present two main Jupyter Notebook workflows that can help in the identification of new T-cell targets against SARS-CoV viruses. In fact, in a cross-reactive case study, our workflows identified a conserved N protein peptide (SPRWYFYYL) recognized by CD8+ T-cells in the context of HLA-B7+. SARS-Arena is available at https://github.com/KavrakiLab/SARS-Arena.