Variations in MHC class I antigen presentation and immunopeptidome selection pathways

Zaitouna, Anita; Kaur, Amanpreet; Raghavan, Malini

doi:10.12688/f1000research.26935.1

Cited by 12 publications

(9 citation statements)

References 93 publications

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“…Human MHC-I molecules are highly polymorphic and have a specific peptide motif preference ( 17 ). In order to determine the HLA structure to which the immunogenic peptide is attached, we used residue scanning module with MM-GBSA method in Schrödinger software (LLC, NY, USA, 2020-1) to select structure with the strongest affinity as the subsequent docking receptor.…”

Section: Methodsmentioning

confidence: 99%

Computer-Based Immunoinformatic Analysis to Predict Candidate T-Cell Epitopes for SARS-CoV-2 Vaccine Design

Mei

Gu²,

Shen³

et al. 2022

Front. Immunol.

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Since the first outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019, its high infectivity led to its prevalence around the world in an exceptionally short time. Efforts have been made to control the ongoing outbreak, and among them, vaccine developments are going on high priority. New clinical trials add to growing evidence that vaccines from many countries were highly effective at preventing SARS-CoV-2 virus infection. One of them is B cell-based vaccines, which were common during a pandemic. However, neutralizing antibody therapy becomes less effective when viruses mutate. In order to tackle the problem, we focused on T-cell immune mechanism. In this study, the mutated strains of the virus were selected globally from India (B.1.617.1 and B.1.617.2), United Kingdom (B.1.1.7), South Africa (B.1.351), and Brazil (P.1), and the overlapping peptides were collected based on mutation sites of S-protein. After that, residue scanning was used to predict the affinity between overlapping peptide and HLA-A*11:01, the most frequent human leukocyte antigen (HLA) allele among the Chinese population. Then, the binding free energy was evaluated with molecular docking to further verify the affinity changes after the mutations happen in the virus genomes. The affinity test results of three epitopes on spike protein from experimental validation were consistent with our predicted results, thereby supporting the inclusion of the epitope 374FSTFKCYGL382 in future vaccine design and providing a useful reference route to improve vaccine development.

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Section: Methodsmentioning

confidence: 99%

Computer-Based Immunoinformatic Analysis to Predict Candidate T-Cell Epitopes for SARS-CoV-2 Vaccine Design

Mei

Gu²,

Shen³

et al. 2022

Front. Immunol.

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“…Tapasin links the modules to the transporter associated with antigen processing (TAP1‐TAP2) subunits. 78 , 79 , 80 , 81 , 82 A low‐resolution cryo‐EM‐based model of the PLC has been obtained (Figure 5A ) 79 and recently used to construct and simulate all‐atom molecular dynamics of the complete human PLC. 81 Additionally, structures of water‐soluble domains of an editing module of the human PLC have been generated based on cryo‐EM images at 3.7 Å resolution.…”

Section: Mhc Class I Antigen Presentation and T Cell Activation By Mu...mentioning

confidence: 99%

Effects of calreticulin mutations on cell transformation and immunity

Desikan

Kaur

Pogozheva

et al. 2023

J Cellular Molecular Medi

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Myeloproliferative neoplasms (MPNs) are cancers involving dysregulated production and function of myeloid lineage hematopoietic cells. Among MPNs, Essential thrombocythemia (ET), Polycythemia Vera (PV) and Myelofibrosis (MF), are driven by mutations that activate the JAK–STAT signalling pathway. Somatic mutations of calreticulin (CRT), an endoplasmic reticulum (ER)‐localized lectin chaperone, are driver mutations in approximately 25% of ET and 35% of MF patients. The MPN‐linked mutant CRT proteins have novel frameshifted carboxy‐domain sequences and lack an ER retention motif, resulting in their secretion. Wild type CRT is a regulator of ER calcium homeostasis and plays a key role in the assembly of major histocompatibility complex (MHC) class I molecules, which are the ligands for antigen receptors of CD8 + T cells. Mutant CRT‐linked oncogenesis results from the dysregulation of calcium signalling in cells and the formation of stable complexes of mutant CRT with myeloproliferative leukemia (MPL) protein, followed by downstream activation of the JAK–STAT signalling pathway. The intricate participation of CRT in ER protein folding, calcium homeostasis and immunity suggests the involvement of multiple mechanisms of mutant CRT‐linked oncogenesis. In this review, we highlight recent findings related to the role of MPN‐linked CRT mutations in the dysregulation of calcium homeostasis, MPL activation and immunity.

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“…Some of these effects can be explained by the interacting surfaces observed in the x-ray structures of chaperoned, peptide-deficient MHC-I complexes ( 23 , 24 ), including a conserved allosteric site underneath the α 2–1 helix revealed by solution nuclear magnetic resonance (NMR) ( 12 ). Furthermore, highly polymorphic MHC-I residues distant to the chaperone binding sites can influence interactions with TAPBPR by modulating the dynamic sampling of an “open” conformation ( 25 , 26 ). Notwithstanding, chaperones can recognize a much broader allelic repertoire of partially folded MHC-I molecules, as shown by deep mutagenesis experiments ( 25 , 27 ).…”

Section: Introductionmentioning

confidence: 99%

Xeno interactions between MHC-I proteins and molecular chaperones enable ligand exchange on a broad repertoire of HLA allotypes

et al. 2023

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Immunological chaperones tapasin and TAP binding protein, related (TAPBPR) play key roles in antigenic peptide optimization and quality control of nascent class I major histocompatibility complex (MHC-I) molecules. The polymorphic nature of MHC-I proteins leads to a range of allelic dependencies on chaperones for assembly and cell-surface expression, limiting chaperone-mediated peptide exchange to a restricted set of human leukocyte antigen (HLA) allotypes. Here, we demonstrate and characterize xeno interactions between a chicken TAPBPR ortholog and a complementary repertoire of HLA allotypes, relative to its human counterpart. We find that TAPBPR orthologs recognize empty MHC-I with broader allele specificity and facilitate peptide exchange by maintaining a reservoir of receptive molecules. Deep mutational scanning of human TAPBPR further identifies gain-of-function mutants, resembling the chicken sequence, which can enhance HLA-A*01:01 expression in situ and promote peptide exchange in vitro. These results highlight that polymorphic sites on MHC-I and chaperone surfaces can be engineered to manipulate their interactions, enabling chaperone-mediated peptide exchange on disease-relevant HLA alleles.

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Variations in MHC class I antigen presentation and immunopeptidome selection pathways

Cited by 12 publications

References 93 publications

Computer-Based Immunoinformatic Analysis to Predict Candidate T-Cell Epitopes for SARS-CoV-2 Vaccine Design

Computer-Based Immunoinformatic Analysis to Predict Candidate T-Cell Epitopes for SARS-CoV-2 Vaccine Design

Effects of calreticulin mutations on cell transformation and immunity

Xeno interactions between MHC-I proteins and molecular chaperones enable ligand exchange on a broad repertoire of HLA allotypes

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