Conserved Non-Pocket Interactions Drive The Diversity of Peptide Presentation By Mhc Class I Molecules

<p>Cytotoxic T-lymphocytes (CTL) can lyse infected or transformed cells through recognition of peptides presented on human leukocyte antigen (HLA) molecules. A thorough understanding of peptide-HLA interactions is needed for improvement of CTL-based immunotherapies. We observed that aspartic acid (D) and glutamic acid (E) at peptide position 4 are highly prevalent in HLA-I peptide ligands, and discovered that they interact with arginine (R) in position 65 and lysine (L) in position 66 of the α1 helix of the binding groove in HLA-A*0201 and HLA-A*2402. Since this interaction differed from well-characterized peptide-HLA anchor interactions mediated by peptide position 2 and the C-terminus, we investigated if the charged interactions between D/E in position 4 and R65 and K66 on the α1 helix of A*0201 and A*2402 are important for peptide antigen presentation. Mutations to R65 and K66 caused loss of HLA cell surface expression, reduced peptide repertoire diversity, and loss of charged interactions between D/E4 and p65-66 in both A*0201 and A*2402. In addition, mutating R65 and/or K66 altered the peptide motifs of both A*0201 and A*2402 specifically in peptide positions 1, 2 and the C-terminus. Peptide binding and stability assays revealed that D/E residues in position 4 contribute significantly to both peptide binding and stability, particularly in peptides with weaker N and C-terminal anchors. Several other HLA-I alleles and MHC molecules from different animal species also showed conservation of R65 and K66, in addition to D/E4 in bound peptide ligands, suggesting that charged interactions between D/E4 and R65/K66 represent a conserved, non-canonical pan-MHC-I anchor interaction that should be accounted for when identifying peptide targets for immunotherapies.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2021

Authors dc:creator

• Jackson, Kyle
• <p>https://orcid.org/0000-0002-3711-2861</p>

Contributors dc:contributor

• Gregory Lizee
• Jagannadha K Sastry
• Juan Fueyo

• Antigen presentation
• Human Leukocyte Antigens
• HLA Class I
• peptide binding stability
• mass spectrometry
• computational modeling
• immunopeptidome
• peptide repertoire diversity
• molecular interactions
• molecular dynamics
• Immunity
• Medicine and Health Sciences
• Other Immunology and Infectious Disease

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1135

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2191