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- EMDB-31618: Cryo-EM structure of a membrane protein(WT) -

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Basic information

Entry
Database: EMDB / ID: EMD-31618
TitleCryo-EM structure of a membrane protein(WT)
Map data
Sample
  • Complex: immune system
    • Protein or peptide: T-cell surface glycoprotein CD3 zeta chain
    • Protein or peptide: T-cell surface glycoprotein CD3 delta chain
    • Protein or peptide: T-cell surface glycoprotein CD3 epsilon chain
    • Protein or peptide: T-cell surface glycoprotein CD3 gamma chain
    • Protein or peptide: T cell receptor alpha variable 12-3,Possible J 11 gene segment,T cell receptor alpha chain constant
    • Protein or peptide: T cell receptor beta variable 6-5,M1-specific T cell receptor beta chain,T cell receptor beta constant 2
  • Ligand: CHOLESTEROL
Function / homology
Function and homology information


regulation of lymphocyte apoptotic process / gamma-delta T cell receptor complex / Fc-gamma receptor III complex / T cell anergy / positive regulation of T cell anergy / positive regulation of cell-cell adhesion mediated by integrin / Fc-gamma receptor signaling pathway / T cell activation involved in immune response / CD4-positive, alpha-beta T cell proliferation / gamma-delta T cell activation ...regulation of lymphocyte apoptotic process / gamma-delta T cell receptor complex / Fc-gamma receptor III complex / T cell anergy / positive regulation of T cell anergy / positive regulation of cell-cell adhesion mediated by integrin / Fc-gamma receptor signaling pathway / T cell activation involved in immune response / CD4-positive, alpha-beta T cell proliferation / gamma-delta T cell activation / negative thymic T cell selection / positive regulation of CD4-positive, alpha-beta T cell proliferation / alpha-beta T cell receptor complex / positive regulation of protein localization to cell surface / positive thymic T cell selection / signal complex assembly / Nef and signal transduction / positive regulation of cell-matrix adhesion / T cell receptor complex / smoothened signaling pathway / establishment or maintenance of cell polarity / positive regulation of interleukin-4 production / dendrite development / Translocation of ZAP-70 to Immunological synapse / Phosphorylation of CD3 and TCR zeta chains / alpha-beta T cell activation / Generation of second messenger molecules / immunological synapse / FCGR activation / PD-1 signaling / Role of phospholipids in phagocytosis / positive regulation of calcium-mediated signaling / T cell receptor binding / negative regulation of smoothened signaling pathway / positive regulation of T cell proliferation / immunoglobulin complex, circulating / immunoglobulin receptor binding / cell surface receptor protein tyrosine kinase signaling pathway / T cell costimulation / positive regulation of interleukin-2 production / T cell activation / cerebellum development / FCGR3A-mediated IL10 synthesis / protein tyrosine kinase binding / complement activation, classical pathway / calcium-mediated signaling / apoptotic signaling pathway / FCGR3A-mediated phagocytosis / antigen binding / response to bacterium / clathrin-coated endocytic vesicle membrane / Regulation of actin dynamics for phagocytic cup formation / SH3 domain binding / transmembrane signaling receptor activity / peptide antigen binding / positive regulation of peptidyl-tyrosine phosphorylation / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / positive regulation of type II interferon production / cell-cell junction / signaling receptor complex adaptor activity / protein transport / Cargo recognition for clathrin-mediated endocytosis / Downstream TCR signaling / protein complex oligomerization / Clathrin-mediated endocytosis / T cell receptor signaling pathway / cell body / antibacterial humoral response / protein-containing complex assembly / regulation of apoptotic process / adaptive immune response / dendritic spine / cell surface receptor signaling pathway / blood microparticle / G protein-coupled receptor signaling pathway / protein heterodimerization activity / external side of plasma membrane / negative regulation of gene expression / positive regulation of gene expression / protein kinase binding / Golgi apparatus / cell surface / endoplasmic reticulum / protein homodimerization activity / extracellular exosome / identical protein binding / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
CD3 gamma/delta subunit, Ig-like domain / T-cell surface glycoprotein CD3 delta chain / T-cell surface glycoprotein CD3 zeta subunit / T-cell surface glycoprotein CD3 zeta subunit/High affinity IgE receptor gamma subunit / T-cell surface glycoprotein CD3 zeta chain / Ig-like domain on T-cell surface glycoprotein CD3 epsilon chain / CD3 protein, epsilon/gamma/delta subunit / Immunoreceptor tyrosine-based activation motif / Phosphorylated immunoreceptor signalling ITAM / ITAM motif mammalian type profile. ...CD3 gamma/delta subunit, Ig-like domain / T-cell surface glycoprotein CD3 delta chain / T-cell surface glycoprotein CD3 zeta subunit / T-cell surface glycoprotein CD3 zeta subunit/High affinity IgE receptor gamma subunit / T-cell surface glycoprotein CD3 zeta chain / Ig-like domain on T-cell surface glycoprotein CD3 epsilon chain / CD3 protein, epsilon/gamma/delta subunit / Immunoreceptor tyrosine-based activation motif / Phosphorylated immunoreceptor signalling ITAM / ITAM motif mammalian type profile. / Immunoreceptor tyrosine-based activation motif / T-cell receptor alpha chain, constant domain / Domain of unknown function (DUF1968) / Immunoglobulin subtype 2 / Immunoglobulin C-2 Type / Immunoglobulin V-Type / Immunoglobulin V-set domain / Immunoglobulin V-set domain / Immunoglobulin subtype / Immunoglobulin / 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
T cell receptor alpha variable 12-3 / T cell receptor beta constant 2 / T cell receptor beta variable 6-5 / Possible J 11 gene segment / T cell receptor alpha chain constant / T-cell surface glycoprotein CD3 delta chain / T-cell surface glycoprotein CD3 epsilon chain / T-cell surface glycoprotein CD3 gamma chain / M1-specific T cell receptor beta chain / T-cell surface glycoprotein CD3 zeta chain
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsChen Y / Zhu Y / Gao W / Zhang A / Guo C / Huang Z
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31825008 China
CitationJournal: Mol Cell / Year: 2022
Title: Cholesterol inhibits TCR signaling by directly restricting TCR-CD3 core tunnel motility.
Authors: Yan Chen / Yuwei Zhu / Xiang Li / Wenbo Gao / Ziqi Zhen / De Dong / Buliao Huang / Zhuo Ma / Anqi Zhang / Xiaocui Song / Yan Ma / Changyou Guo / Fan Zhang / Zhiwei Huang /
Abstract: Cholesterol molecules specifically bind to the resting αβTCR to inhibit cytoplasmic CD3ζ ITAM phosphorylation through sequestering the TCR-CD3 complex in an inactive conformation. The mechanisms ...Cholesterol molecules specifically bind to the resting αβTCR to inhibit cytoplasmic CD3ζ ITAM phosphorylation through sequestering the TCR-CD3 complex in an inactive conformation. The mechanisms of cholesterol-mediated inhibition of TCR-CD3 and its activation remain unclear. Here, we present cryoelectron microscopy structures of cholesterol- and cholesterol sulfate (CS)-inhibited TCR-CD3 complexes and an auto-active TCR-CD3 variant. The structures reveal that cholesterol molecules act like a latch to lock CD3ζ into an inactive conformation in the membrane. Mutations impairing binding of cholesterol molecules to the tunnel result in the movement of the proximal C terminus of the CD3ζ transmembrane helix, thereby activating the TCR-CD3 complex in human cells. Together, our data reveal the structural basis of TCR inhibition by cholesterol, illustrate how the cholesterol-binding tunnel is allosterically coupled to TCR triggering, and lay a foundation for the development of immunotherapies through directly targeting the TCR-CD3 complex.
History
DepositionAug 3, 2021-
Header (metadata) releaseJul 27, 2022-
Map releaseJul 27, 2022-
UpdateJul 27, 2022-
Current statusJul 27, 2022Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_31618.png

Downloads & links

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Map

FileDownload / File: emd_31618.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.1 Å
Density
Contour LevelBy AUTHOR: 0.0462
Minimum - Maximum-0.16072492 - 0.2668755
Average (Standard dev.)-0.00011173577 (±0.0063981386)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 281.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : immune system

EntireName: immune system
Components
  • Complex: immune system
    • Protein or peptide: T-cell surface glycoprotein CD3 zeta chain
    • Protein or peptide: T-cell surface glycoprotein CD3 delta chain
    • Protein or peptide: T-cell surface glycoprotein CD3 epsilon chain
    • Protein or peptide: T-cell surface glycoprotein CD3 gamma chain
    • Protein or peptide: T cell receptor alpha variable 12-3,Possible J 11 gene segment,T cell receptor alpha chain constant
    • Protein or peptide: T cell receptor beta variable 6-5,M1-specific T cell receptor beta chain,T cell receptor beta constant 2
  • Ligand: CHOLESTEROL

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Supramolecule #1: immune system

SupramoleculeName: immune system / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#6
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Macromolecule #1: T-cell surface glycoprotein CD3 zeta chain

MacromoleculeName: T-cell surface glycoprotein CD3 zeta chain / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 18.81052 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MKWKALFTAA ILQAQLPITE AQSFGLLDPK LCYLLDGILF IYGVILTALF LRVKFSRSAD APAYQQGQNQ LYNELNLGRR EEYDVLDKR RGRDPEMGGK PQRRKNPQEG LYNELQKDKM AEAYSEIGMK GERRRGKGHD GLYQGLSTAT KDTYDALHMQ A LPPRS

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Macromolecule #2: T-cell surface glycoprotein CD3 delta chain

MacromoleculeName: T-cell surface glycoprotein CD3 delta chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 18.949537 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MEHSTFLSGL VLATLLSQVS PFKIPIEELE DRVFVNCNTS ITWVEGTVGT LLSDITRLDL GKRILDPRGI YRCNGTDIYK DKESTVQVH YRMCQSCVEL DPATVAGIIV TDVIATLLLA LGVFCFAGHE TGRLSGAADT QALLRNDQVY QPLRDRDDAQ Y SHLGGNWA RNK

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Macromolecule #3: T-cell surface glycoprotein CD3 epsilon chain

MacromoleculeName: T-cell surface glycoprotein CD3 epsilon chain / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.174227 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MQSGTHWRVL GLCLLSVGVW GQDGNEEMGG ITQTPYKVSI SGTTVILTCP QYPGSEILWQ HNDKNIGGDE DDKNIGSDED HLSLKEFSE LEQSGYYVCY PRGSKPEDAN FYLYLRARVC ENCMEMDVMS VATIVIVDIC ITGGLLLLVY YWSKNRKAKA K PVTRGAGA ...String:
MQSGTHWRVL GLCLLSVGVW GQDGNEEMGG ITQTPYKVSI SGTTVILTCP QYPGSEILWQ HNDKNIGGDE DDKNIGSDED HLSLKEFSE LEQSGYYVCY PRGSKPEDAN FYLYLRARVC ENCMEMDVMS VATIVIVDIC ITGGLLLLVY YWSKNRKAKA K PVTRGAGA GGRQRGQNKE RPPPVPNPDY EPIRKGQRDL YSGLNQRRI

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Macromolecule #4: T-cell surface glycoprotein CD3 gamma chain

MacromoleculeName: T-cell surface glycoprotein CD3 gamma chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 20.493457 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MEQGKGLAVL ILAIILLQGT LAQSIKGNHL VKVYDYQEDG SVLLTCDAEA KNITWFKDGK MIGFLTEDKK KWNLGSNAKD PRGMYQCKG SQNKSKPLQV YYRMCQNCIE LNAATISGFL FAEIVSIFVL AVGVYFIAGQ DGVRQSRASD KQTLLPNDQL Y QPLKDRED DQYSHLQGNQ LRRN

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Macromolecule #5: T cell receptor alpha variable 12-3,Possible J 11 gene segment,T ...

MacromoleculeName: T cell receptor alpha variable 12-3,Possible J 11 gene segment,T cell receptor alpha chain constant
type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 30.763717 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MKSLRVLLVI LWLQLSWVWS QQKEVEQDPG PLSVPEGAIV SLNCTYSNSA FQYFMWYRQY SRKGPELLMY TYSSGNKEDG RFTAQVDKS SKYISLFIRD SQPSDSATYL CAMSKGYSTL TFGKGTMLLV SPDIQNPDPA VYQLRDSKSS DKSVCLFTDF D SQTNVSQS ...String:
MKSLRVLLVI LWLQLSWVWS QQKEVEQDPG PLSVPEGAIV SLNCTYSNSA FQYFMWYRQY SRKGPELLMY TYSSGNKEDG RFTAQVDKS SKYISLFIRD SQPSDSATYL CAMSKGYSTL TFGKGTMLLV SPDIQNPDPA VYQLRDSKSS DKSVCLFTDF D SQTNVSQS KDSDVYITDK TVLDMRSMDF KSNSAVAWSN KSDFACANAF NNSIIPEDTF FPSPESSCDV KLVEKSFETD TN LNFQNLS VIGFRILLLK VAGFNLLMTL RLWSS

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Macromolecule #6: T cell receptor beta variable 6-5,M1-specific T cell receptor bet...

MacromoleculeName: T cell receptor beta variable 6-5,M1-specific T cell receptor beta chain,T cell receptor beta constant 2
type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 34.614051 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MSISLLCCAA LSLLWAGPVN AGVTQTPKFQ VLKTGQSMTL QCAQDMNHEY MSWYRQDPGM GLRLIHYSVG AGITDQGEVP NGYNVSRST TEDFPLRLLS AAPSQTSVYF CASRRRQGAS GEQYFGPGTR LTVTEDLKNV FPPEVAVFEP SEAEISHTQK A TLVCLATG ...String:
MSISLLCCAA LSLLWAGPVN AGVTQTPKFQ VLKTGQSMTL QCAQDMNHEY MSWYRQDPGM GLRLIHYSVG AGITDQGEVP NGYNVSRST TEDFPLRLLS AAPSQTSVYF CASRRRQGAS GEQYFGPGTR LTVTEDLKNV FPPEVAVFEP SEAEISHTQK A TLVCLATG FYPDHVELSW WVNGKEVHSG VSTDPQPLKE QPALNDSRYC LSSRLRVSAT FWQNPRNHFR CQVQFYGLSE ND EWTQDRA KPVTQIVSAE AWGRADCGFT SESYQQGVLS ATILYEILLG KATLYAVLVS ALVLMAMVKR KDSRG

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Macromolecule #7: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 7 / Number of copies: 2 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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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: NITROGEN

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 550597
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING

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