Interaction of TAPBPR, a tapasin homolog, with MHC-I molecules promotes peptide editing

Morozov, Giora I.; Zhao, Huaying; Mage, Michael G.; Boyd, Lisa F.; Jiang, Jiansheng; Dolan, Michael; Venna, Ramesh; Norcross, Michael A.; McMurtrey, Curtis P.; Hildebrand, William H.; Schuck, Peter; Natarajan, Kannan; Margulies, David H.

doi:10.1073/pnas.1519894113

Cited by 82 publications

(156 citation statements)

References 54 publications

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“…[3][4][5][6]25 Antigen processing and presentation in humans and mice have differences that are well known. For example, as shown elegantly, recently, 39 human and murine tapasin diverge in sequence. These tapasins are chaperones of MHC class I molecules.…”

Section: Discussionmentioning

confidence: 92%

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Protein nanovaccine confers robust immunity against Toxoplasma

Bissati

Zhou

Paulillo³

et al. 2017

npj Vaccines

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We designed and produced a self-assembling protein nanoparticle. This self-assembling protein nanoparticle contains five CD8+ HLA-A03-11 supertypes-restricted epitopes from antigens expressed during Toxoplasma gondii’s lifecycle, the universal CD4+ T cell epitope PADRE, and flagellin as a scaffold and TLR5 agonist. These CD8+ T cell epitopes were separated by N/KAAA spacers and optimized for proteasomal cleavage. Self-assembling protein nanoparticle adjuvanted with TLR4 ligand-emulsion GLA-SE were evaluated for their efficacy in inducing IFN-γ responses and protection of HLA-A*1101 transgenic mice against T. gondii. Immunization, using self-assembling protein nanoparticle-GLA-SE, activated CD8+ T cells to produce IFN-γ. Self-assembling protein nanoparticle-GLA-SE also protected HLA-A*1101 transgenic mice against subsequent challenge with Type II parasites. Hence, combining CD8+ T cell-eliciting peptides and PADRE into a multi-epitope protein that forms a nanoparticle, administered with GLA-SE, leads to efficient presentation by major histocompatibility complex Class I and II molecules. Furthermore, these results suggest that activation of TLR4 and TLR5 could be useful for development of vaccines that elicit T cells to prevent toxoplasmosis in humans.

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Section: Discussionmentioning

confidence: 92%

“…Newer murine models with human tapasin and proteasome might improve vaccine potency and be more relevant to human vaccine development. 39 Alternatively, our optimized cleavage sites, based on human infection, using human PBMC, may work as effectively in our HLA-A*1101 mice. This comparison will be tested in future studies.…”

Section: Discussionmentioning

confidence: 99%

Protein nanovaccine confers robust immunity against Toxoplasma

Bissati

Zhou

Paulillo³

et al. 2017

npj Vaccines

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“…Peptides that are too long can be trimmed by an ER resident aminopeptidase, ERAP1 (and ERAP 2 in some species)[27–29] before consideration by MHC I molecules that are either in the peptide-loading complex or associating with another tapasin look-alike chaperone in the ER called TAPBPR. Like tapasin, TAPBPR also shapes the peptide repertoire on MHC I molecules 30,31]. Very interestingly, binding of peptides longer than 8–9 residues, but not shorter ones, triggers a conformational change in ERAP1 that activates its hydrolysis [32–34].…”

Section: How To Present Your Inner Self? Mhc Class I Moleculesmentioning

confidence: 99%

Present Yourself! By MHC Class I and MHC Class II Molecules

Rock

Reits

Neefjes

2016

Trends in Immunology

561

462

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Since the discovery of major histocompatibility complex (MHC) molecules, it took some 40 years to arrive at a coherent picture of how MHC class I and MHC class II molecules really work. This is a story of proteases and MHC-like chaperones that support the MHC class I and II molecules in presenting peptides to the immune system. We now understand that the MHC system shapes both the repertoire of presented peptides and the subsequent T cell responses, with important implications ranging from transplant rejection to tumor immunotherapies. Here we present an illustrated review on the ins and outs of MHC class I and MHC class II antigen presentation.

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“…The discovery that TAPBPR can function as a peptide exchange catalyst outside the peptideloading complex and can maintain empty MHC-I molecules in a peptide-receptive conformation has opened a new window to study the peptide loading process in a range of detailed functional and mechanistic studies (4,12,13). Structural insights into static snapshots of MHC-I/chaperone complexes have been gleaned by X-ray crystallography (14,15) and cryoEM (16).…”

Section: Introductionmentioning

confidence: 99%

Molecular determinants of chaperone interactions on MHC-I for folding and antigen repertoire selection

McShan¹,

Devlin²,

Overall³

et al. 2019

Preprint

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Highlights Deep mutagenesis identifies a conformational disulfide-linked epitope as the main requirement for association of nascent MHC-I molecules with the TAPBPR chaperone  Analysis of μs-ms timescale conformational dynamics by methyl NMR reveals allelespecific profiles at the TAPBPR interaction surfaces of peptide-loaded MHC-I molecules  μs-ms dynamics dictate the specificity of TAPBPR interactions for different MHC-I alleles through the sampling of a minor, "excited state" conformation  Restriction of dynamics though an engineered disulfide bond abrogates interactions with TAPBPR, both in solution and on a cellular membrane Keywords Major Histocompatibility Complex • MHC-I • NMR spectroscopy • protein dynamics • molecular chaperone • TAPBPR • peptide editing • deep mutagenesis mapping • conformational landscape • peptide repertoire Graphical Abstract AbstractThe interplay between a highly polymorphic set of MHC-I alleles and molecular chaperones shapes the repertoire of peptide antigens displayed on the cell surface for T cell surveillance.Here, we demonstrate that the molecular chaperone TAPBPR associates with a broad range of partially folded MHC-I species inside the cell. Bimolecular fluorescence complementation and deep mutational scanning reveal that TAPBPR recognition is polarized towards one side of the peptide-binding groove, and depends on the formation of a conserved MHC-I disulfide epitope in the α 2 domain. Conversely, thermodynamic measurements of TAPBPR binding for a representative set of properly conformed, peptide-loaded molecules suggest a narrower MHC-I specificity range. Using solution NMR, we find that the extent of dynamics at "hotspot" surfaces confers TAPBPR recognition of a sparsely populated MHC-I state attained through a global conformational change. Consistently, restriction of MHC-I groove plasticity through the introduction of a disulfide bond between the α 1 /α 2 helices abrogates TAPBPR binding, both in solution and on a cellular membrane, while intracellular binding is tolerant of many destabilizing MHC-I substitutions. Our data support parallel TAPBPR functions of i) chaperoning unstable MHC-I molecules at early stages of their folding process, akin to a holdase with broad allelespecificity, and ii) editing the peptide cargo of properly conformed MHC-I molecules en route to the surface, which demonstrates a narrower specificity. Our results suggest that TAPBPR exploits localized structural adaptations, both near and distant to the peptide-binding groove, to selectively recognize discrete conformational states sampled by MHC-I alleles, towards editing Sithe repertoire of displayed antigens. Significance StatementThe human population contains thousands of MHC-I alleles, showing a range of dependencies on molecular chaperones for loading of their peptide cargo, which are then displayed on the cell surface for T cell surveillance. Using the chaperone TAPBPR as a model, we combine deep mutagenesis with functional and biophysical data, especially solution NMR, to provide a compl...

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Interaction of TAPBPR, a tapasin homolog, with MHC-I molecules promotes peptide editing

Cited by 82 publications

References 54 publications

Protein nanovaccine confers robust immunity against Toxoplasma

Protein nanovaccine confers robust immunity against Toxoplasma

Present Yourself! By MHC Class I and MHC Class II Molecules

Molecular determinants of chaperone interactions on MHC-I for folding and antigen repertoire selection

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