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- EMDB-45360: Cryo-EM structure of TAP binding protein related (TAPBPR) in comp... -

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Entry
Database: EMDB / ID: EMD-45360
TitleCryo-EM structure of TAP binding protein related (TAPBPR) in complex with HLA-A*02:01 bound to a suboptimal peptide.
Map dataCryo-EM structure of TAP binding protein related (TAPBPR) in complex with HLA-A*02:01 bound to a suboptimal peptide.
Sample
  • Complex: Complex of peptide loaded HLA-A*02:01/beta-2-microglobulin in complex with human TAPBPR.
    • Protein or peptide: MHC class I antigen
    • Protein or peptide: Beta-2-microglobulin
    • Protein or peptide: Tapasin-related protein
    • Protein or peptide: LYS-ILE-LEU-GLY-PHE-VAL
KeywordsAntigen processing and presentation / TAP binding protein related / MHC-I / Chaperone / IMMUNE SYSTEM
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.0 Å
AuthorsPumroy RP / Mallik L / Sun Y / Moiseenkova-Bell YV / Sgourakis NG
Funding support United States, United Kingdom, 6 items
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, 2024-
Header (metadata) releaseJan 22, 2025-
Map releaseJan 22, 2025-
UpdateJan 29, 2025-
Current statusJan 29, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_45360.png

Downloads & links

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Map

FileDownload / File: emd_45360.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationCryo-EM structure of TAP binding protein related (TAPBPR) in complex with HLA-A*02:01 bound to a suboptimal peptide.
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.84 Å/pix.
x 256 pix.
= 214.016 Å		0.84 Å/pix.
x 256 pix.
= 214.016 Å		0.84 Å/pix.
x 256 pix.
= 214.016 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.836 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0129
Minimum - Maximum-0.052104935 - 0.086267605
Average (Standard dev.)-0.000058880876 (±0.0022281113)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 214.016 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: Half Map A

Fileemd_45360_half_map_1.map
AnnotationHalf Map A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Half Map B

Fileemd_45360_half_map_2.map
AnnotationHalf Map B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of peptide loaded HLA-A*02:01/beta-2-microglobulin in com...

EntireName: Complex of peptide loaded HLA-A*02:01/beta-2-microglobulin in complex with human TAPBPR.
Components
  • Complex: Complex of peptide loaded HLA-A*02:01/beta-2-microglobulin in complex with human TAPBPR.
    • Protein or peptide: MHC class I antigen
    • Protein or peptide: Beta-2-microglobulin
    • Protein or peptide: Tapasin-related protein
    • Protein or peptide: LYS-ILE-LEU-GLY-PHE-VAL

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Supramolecule #1: Complex of peptide loaded HLA-A*02:01/beta-2-microglobulin in com...

SupramoleculeName: Complex of peptide loaded HLA-A*02:01/beta-2-microglobulin in complex with human TAPBPR.
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: MHC class I antigen

MacromoleculeName: MHC class I antigen / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 32.128602 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGSHSMRYFF TSVSRPGRGE PRFIAVGYVD DTQFVRFDSD AASQRMEPRA PWIEQEGPEY WDGETRKVKA HSQTHRVDLG TLRGYYNQS EAGSHTVQRM YGCDVGSDWR FLRGYHQYAY DCKDYIALKE DLRSWTAADM AAQTTKHKWE AAHVAEQLRA Y LEGTCVEW ...String:
MGSHSMRYFF TSVSRPGRGE PRFIAVGYVD DTQFVRFDSD AASQRMEPRA PWIEQEGPEY WDGETRKVKA HSQTHRVDLG TLRGYYNQS EAGSHTVQRM YGCDVGSDWR FLRGYHQYAY DCKDYIALKE DLRSWTAADM AAQTTKHKWE AAHVAEQLRA Y LEGTCVEW LRRYLENGKE TLQRTDAPKT HMTHHAVSDH EATLRCWALS FYPAEITLTW QRDGEDQTQD TELVETRPAG DG TFQKWAA VVVPSGQEQR YTCHVQHEGL PKPLTLRWEP

UniProtKB: MHC class I antigen

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Macromolecule #2: Beta-2-microglobulin

MacromoleculeName: Beta-2-microglobulin / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.58196 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
IQRTPKIQVY SRHPAENGKS NFLNCYVSGF CPSDIEVDLL KNGERIEKVE HSDLSFSKDW SFYLLYYTEF TPTEKDEYAC RVNHVTLSQ PKIVKWDRD

UniProtKB: Beta-2-microglobulin

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Macromolecule #3: Tapasin-related protein

MacromoleculeName: Tapasin-related protein / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.191469 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: KPHPAEGQWR AVDVVLDCFL VKDGAHRGAL ASSEDRARAS LVLKQVPVLD DGSLEDFTDF QGGTLAQDDP PIIFEASVDL VQIPQAEAL LHADSSGKEV TCEIFRYFLQ MTETTVKTAA WFMANVQVSG GGPSISLVMK TPRVAKNEVL WHPTLNLPLS P QGTVRTAV ...String:
KPHPAEGQWR AVDVVLDCFL VKDGAHRGAL ASSEDRARAS LVLKQVPVLD DGSLEDFTDF QGGTLAQDDP PIIFEASVDL VQIPQAEAL LHADSSGKEV TCEIFRYFLQ MTETTVKTAA WFMANVQVSG GGPSISLVMK TPRVAKNEVL WHPTLNLPLS P QGTVRTAV EFQVMTQTQS LSFLLGSSAS LDCGFSMAPG LDLISVEWRL QHLGRGQLVY SWTAGQGQAV RKGATLEPAQ LG MARDASL TLPGLTIQDE GTYICQITTS LYQAQQIIQL NIQASPKVRL SLANEALLPT LICDIAGYYP LDVVVTWTRE ELG GSPAQV SGASFSSLRQ SVAGTYSISS SLTAEPGSAG ATYTCQVTHI SLEEPLGAST QVVPPERR

UniProtKB: Tapasin-related protein

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Macromolecule #4: LYS-ILE-LEU-GLY-PHE-VAL

MacromoleculeName: LYS-ILE-LEU-GLY-PHE-VAL / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 824.041 Da
SequenceString:
KILGFVF

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 40.5 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 20.0 µm / Nominal defocus min: 8.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 88714
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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