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- PDB-9c96: Cryo-EM structure of TAP binding protein related (TAPBPR) in comp... -

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Basic information

Entry
Database: PDB / ID: 9c96
TitleCryo-EM structure of TAP binding protein related (TAPBPR) in complex with HLA-A*02:01 bound to a suboptimal peptide.
Components
  • Beta-2-microglobulin
  • LYS-ILE-LEU-GLY-PHE-VAL
  • MHC class I antigen
  • Tapasin-related protein
KeywordsIMMUNE SYSTEM / Antigen processing and presentation / TAP binding protein related / MHC-I / Chaperone
Function / homology
Function and homology information


negative regulation of antigen processing and presentation of peptide antigen via MHC class I / MHC class I protein complex binding / TAP complex binding / : / : / positive regulation of receptor binding / early endosome lumen / Nef mediated downregulation of MHC class I complex cell surface expression / negative regulation of receptor binding / DAP12 interactions ...negative regulation of antigen processing and presentation of peptide antigen via MHC class I / MHC class I protein complex binding / TAP complex binding / : / : / positive regulation of receptor binding / early endosome lumen / Nef mediated downregulation of MHC class I complex cell surface expression / negative regulation of receptor binding / DAP12 interactions / cellular response to iron ion / Endosomal/Vacuolar pathway / Antigen Presentation: Folding, assembly and peptide loading of class I MHC / peptide antigen assembly with MHC class II protein complex / cellular response to iron(III) ion / antigen processing and presentation of exogenous protein antigen via MHC class Ib, TAP-dependent / MHC class II protein complex / negative regulation of forebrain neuron differentiation / ER to Golgi transport vesicle membrane / peptide antigen assembly with MHC class I protein complex / regulation of erythrocyte differentiation / regulation of iron ion transport / MHC class I peptide loading complex / response to molecule of bacterial origin / HFE-transferrin receptor complex / T cell mediated cytotoxicity / antigen processing and presentation of endogenous peptide antigen via MHC class I / positive regulation of T cell cytokine production / antigen processing and presentation of exogenous peptide antigen via MHC class II / MHC class I protein complex / positive regulation of immune response / peptide antigen binding / negative regulation of neurogenesis / positive regulation of T cell mediated cytotoxicity / positive regulation of receptor-mediated endocytosis / multicellular organismal-level iron ion homeostasis / positive regulation of T cell activation / cellular response to nicotine / specific granule lumen / recycling endosome membrane / phagocytic vesicle membrane / positive regulation of cellular senescence / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / negative regulation of epithelial cell proliferation / Interferon gamma signaling / MHC class II protein complex binding / positive regulation of protein binding / Modulation by Mtb of host immune system / late endosome membrane / sensory perception of smell / tertiary granule lumen / DAP12 signaling / negative regulation of neuron projection development / iron ion transport / T cell differentiation in thymus / ER-Phagosome pathway / protein refolding / early endosome membrane / protein homotetramerization / amyloid fibril formation / intracellular iron ion homeostasis / learning or memory / Amyloid fiber formation / endoplasmic reticulum lumen / Golgi membrane / external side of plasma membrane / lysosomal membrane / focal adhesion / Neutrophil degranulation / SARS-CoV-2 activates/modulates innate and adaptive immune responses / structural molecule activity / endoplasmic reticulum / Golgi apparatus / protein homodimerization activity / extracellular space / extracellular exosome / extracellular region / identical protein binding / membrane / plasma membrane / cytosol
Similarity search - Function
: / MHC class I alpha chain, alpha1 alpha2 domains / Class I Histocompatibility antigen, domains alpha 1 and 2 / Beta-2-Microglobulin / : / MHC class I-like antigen recognition-like / MHC class I-like antigen recognition-like superfamily / Immunoglobulin V-set domain / MHC classes I/II-like antigen recognition protein / Immunoglobulin V-set domain ...: / MHC class I alpha chain, alpha1 alpha2 domains / Class I Histocompatibility antigen, domains alpha 1 and 2 / Beta-2-Microglobulin / : / MHC class I-like antigen recognition-like / MHC class I-like antigen recognition-like superfamily / Immunoglobulin V-set domain / MHC classes I/II-like antigen recognition protein / Immunoglobulin V-set domain / : / Immunoglobulin subtype / Immunoglobulin / Immunoglobulin/major histocompatibility complex, conserved site / Immunoglobulins and major histocompatibility complex proteins signature. / Immunoglobulin C-Type / Immunoglobulin C1-set / Immunoglobulin C1-set domain / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Beta-2-microglobulin / MHC class I antigen / Tapasin-related protein
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsPumroy, R.P. / Mallik, L. / Sun, Y. / Moiseenkova-Bell, Y.V. / Sgourakis, N.G.
Funding support United States, United Kingdom, 6items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01Al143997 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM125034 United States
Cancer Research UKCGCATF-2021/100002 United Kingdom
National Institutes of Health/National Cancer Institute (NIH/NCI)CA278687-01 United States
The Mark Foundation United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM144120 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: CryoEM structure of an MHC-I/TAPBPR peptide-bound intermediate reveals the mechanism of antigen proofreading.
Authors: Yi Sun / Ruth A Pumroy / Leena Mallik / Apala Chaudhuri / Chloe Wang / Daniel Hwang / Julia N Danon / Kimia Dasteh Goli / Vera Y Moiseenkova-Bell / Nikolaos G Sgourakis /
Abstract: Class I major histocompatibility complex (MHC-I) proteins play a pivotal role in adaptive immunity by displaying epitopic peptides to CD8+ T cells. The chaperones tapasin and TAPBPR promote the ...Class I major histocompatibility complex (MHC-I) proteins play a pivotal role in adaptive immunity by displaying epitopic peptides to CD8+ T cells. The chaperones tapasin and TAPBPR promote the selection of immunogenic antigens from a large pool of intracellular peptides. Interactions of chaperoned MHC-I molecules with incoming peptides are transient in nature, and as a result, the precise antigen proofreading mechanism remains elusive. Here, we leverage a high-fidelity TAPBPR variant and conformationally stabilized MHC-I, to determine the solution structure of the human antigen editing complex bound to a peptide decoy by cryogenic electron microscopy (cryo-EM) at an average resolution of 3.0 Å. Antigen proofreading is mediated by transient interactions formed between the nascent peptide binding groove with the P2/P3 peptide anchors, where conserved MHC-I residues stabilize incoming peptides through backbone-focused contacts. Finally, using our high-fidelity chaperone, we demonstrate robust peptide exchange on the cell surface across multiple clinically relevant human MHC-I allomorphs. Our work has important ramifications for understanding the selection of immunogenic epitopes for T cell screening and vaccine design applications.
History
DepositionJun 13, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 22, 2025Provider: repository / Type: Initial release
Revision 1.1Jan 29, 2025Group: Data collection / Structure summary / Category: audit_author / em_admin / em_author_list
Item: _audit_author.name / _em_admin.last_update / _em_author_list.author

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: MHC class I antigen
B: Beta-2-microglobulin
C: Tapasin-related protein
D: LYS-ILE-LEU-GLY-PHE-VAL


Theoretical massNumber of molelcules
Total (without water)85,7264
Polymers85,7264
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein MHC class I antigen


Mass: 32128.602 Da / Num. of mol.: 1 / Mutation: G121C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HLA-A / Production host: Escherichia coli (E. coli) / References: UniProt: Q8WLS4
#2: Protein Beta-2-microglobulin


Mass: 11581.960 Da / Num. of mol.: 1 / Mutation: H31C
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: B2M, CDABP0092, HDCMA22P / Production host: Escherichia coli (E. coli) / References: UniProt: P61769
#3: Protein Tapasin-related protein / TAPASIN-R / TAP-binding protein-like / TAP-binding protein-related protein / TAPBP-R / Tapasin-like


Mass: 41191.469 Da / Num. of mol.: 1 / Mutation: C94S, S104F, K211L,R270Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TAPBPL / Production host: Escherichia coli (E. coli) / References: UniProt: Q9BX59
#4: Protein/peptide LYS-ILE-LEU-GLY-PHE-VAL


Mass: 824.041 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Complex of peptide loaded HLA-A*02:01/beta-2-microglobulin in complex with human TAPBPR.
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 20000 nm / Nominal defocus min: 8000 nm
Image recordingElectron dose: 40.5 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 88714 / Symmetry type: POINT
RefinementCross valid method: NONE

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