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- EMDB-22344: Structure of human CD19-CD81 co-receptor complex bound to coltuxi... -

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Basic information

Entry
Database: EMDB / ID: EMD-22344
TitleStructure of human CD19-CD81 co-receptor complex bound to coltuximab Fab fragment
Map data
Sample
  • Complex: Complex of B cell co-receptor CD19 bound to the tetraspanin CD81 and coltuximab Fab fragment
    • Complex: B cell co-receptor CD19 bound to the tetraspanin CD81
      • Protein or peptide: B-lymphocyte antigen CD19
      • Protein or peptide: CD81 antigen
    • Complex: coltuximab Fab fragment
      • Protein or peptide: Coltuximab Heavy Chain
      • Protein or peptide: Coltuximab Light Chain
Function / homology
Function and homology information


regulation of B cell activation / positive regulation of adaptive immune memory response / positive regulation of protein catabolic process in the vacuole / antigen receptor-mediated signaling pathway / CD4-positive, alpha-beta T cell costimulation / osteoclast fusion / B-1 B cell differentiation / positive regulation of B cell receptor signaling pathway / myoblast fusion involved in skeletal muscle regeneration / positive regulation of inflammatory response to antigenic stimulus ...regulation of B cell activation / positive regulation of adaptive immune memory response / positive regulation of protein catabolic process in the vacuole / antigen receptor-mediated signaling pathway / CD4-positive, alpha-beta T cell costimulation / osteoclast fusion / B-1 B cell differentiation / positive regulation of B cell receptor signaling pathway / myoblast fusion involved in skeletal muscle regeneration / positive regulation of inflammatory response to antigenic stimulus / regulation of B cell receptor signaling pathway / positive regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell / regulation of macrophage migration / macrophage fusion / transferrin receptor binding / immunological synapse formation / positive regulation of T-helper 2 cell cytokine production / protein localization to lysosome / tetraspanin-enriched microdomain / B cell proliferation involved in immune response / positive regulation of protein exit from endoplasmic reticulum / MHC class II protein binding / humoral immune response mediated by circulating immunoglobulin / positive regulation of CD4-positive, alpha-beta T cell proliferation / cholesterol binding / positive regulation of T cell receptor signaling pathway / cellular response to low-density lipoprotein particle stimulus / immunological synapse / immunoglobulin mediated immune response / positive regulation of B cell proliferation / positive regulation of receptor clustering / basal plasma membrane / positive regulation of release of sequestered calcium ion into cytosol / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Regulation of Complement cascade / protein localization to plasma membrane / B cell receptor signaling pathway / regulation of protein stability / receptor internalization / Constitutive Signaling by Aberrant PI3K in Cancer / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / integrin binding / PIP3 activates AKT signaling / MHC class II protein complex binding / virus receptor activity / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / basolateral plasma membrane / vesicle / positive regulation of MAPK cascade / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / membrane raft / external side of plasma membrane / focal adhesion / positive regulation of transcription by RNA polymerase II / protein-containing complex / extracellular exosome / membrane / plasma membrane
Similarity search - Function
B-lymphocyte antigen CD19 / Tetraspanin, conserved site / Transmembrane 4 family signature. / Tetraspanin, animals / Tetraspanin, EC2 domain superfamily / Tetraspanin/Peripherin / Tetraspanin family / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. ...B-lymphocyte antigen CD19 / Tetraspanin, conserved site / Transmembrane 4 family signature. / Tetraspanin, animals / Tetraspanin, EC2 domain superfamily / Tetraspanin/Peripherin / Tetraspanin family / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
B-lymphocyte antigen CD19 / CD81 antigen
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsSusa KJ / Rawson S / Kruse AC / Blacklow SC
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL 147459 United States
National Institutes of Health/Office of the DirectorDP5 OD021345 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R35 CA220340 United States
CitationJournal: Science / Year: 2021
Title: Cryo-EM structure of the B cell co-receptor CD19 bound to the tetraspanin CD81.
Authors: Katherine J Susa / Shaun Rawson / Andrew C Kruse / Stephen C Blacklow /
Abstract: Signaling through the CD19-CD81 co-receptor complex, in combination with the B cell receptor, is a critical determinant of B cell development and activation. It is unknown how CD81 engages CD19 to ...Signaling through the CD19-CD81 co-receptor complex, in combination with the B cell receptor, is a critical determinant of B cell development and activation. It is unknown how CD81 engages CD19 to enable co-receptor function. Here, we report a 3.8-angstrom structure of the CD19-CD81 complex bound to a therapeutic antigen-binding fragment, determined by cryo-electron microscopy (cryo-EM). The structure includes both the extracellular domains and the transmembrane helices of the complex, revealing a contact interface between the ectodomains that drives complex formation. Upon binding to CD19, CD81 opens its ectodomain to expose a hydrophobic CD19-binding surface and reorganizes its transmembrane helices to occlude a cholesterol binding pocket present in the apoprotein. Our data reveal the structural basis for CD19-CD81 complex assembly, providing a foundation for rational design of therapies for B cell dysfunction.
History
DepositionJul 23, 2020-
Header (metadata) releaseJan 20, 2021-
Map releaseJan 20, 2021-
UpdateJan 20, 2021-
Current statusJan 20, 2021Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.27
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.27
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7jic
  • Surface level: 0.3
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_22344.png

Downloads & links

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Map

FileDownload / File: emd_22344.map.gz / Format: CCP4 / Size: 155.3 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.825 Å
Density
Contour LevelBy AUTHOR: 0.359 / Movie #1: 0.27
Minimum - Maximum-1.1148511 - 1.9569672
Average (Standard dev.)0.0018598629 (±0.033939283)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions344344344
Spacing344344344
CellA=B=C: 283.8 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8250.8250.825
M x/y/z344344344
origin x/y/z0.0000.0000.000
length x/y/z283.800283.800283.800
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ300300300
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS344344344
D min/max/mean-1.1151.9570.002

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Supplemental data

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Half map: #1

Fileemd_22344_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_22344_half_map_2.map
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 B cell co-receptor CD19 bound to the tetraspanin CD81 ...

EntireName: Complex of B cell co-receptor CD19 bound to the tetraspanin CD81 and coltuximab Fab fragment
Components
  • Complex: Complex of B cell co-receptor CD19 bound to the tetraspanin CD81 and coltuximab Fab fragment
    • Complex: B cell co-receptor CD19 bound to the tetraspanin CD81
      • Protein or peptide: B-lymphocyte antigen CD19
      • Protein or peptide: CD81 antigen
    • Complex: coltuximab Fab fragment
      • Protein or peptide: Coltuximab Heavy Chain
      • Protein or peptide: Coltuximab Light Chain

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Supramolecule #1: Complex of B cell co-receptor CD19 bound to the tetraspanin CD81 ...

SupramoleculeName: Complex of B cell co-receptor CD19 bound to the tetraspanin CD81 and coltuximab Fab fragment
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Molecular weightTheoretical: 110 KDa

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Supramolecule #2: B cell co-receptor CD19 bound to the tetraspanin CD81

SupramoleculeName: B cell co-receptor CD19 bound to the tetraspanin CD81 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: Expi293F

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Supramolecule #3: coltuximab Fab fragment

SupramoleculeName: coltuximab Fab fragment / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3-#4
Source (natural)Organism: Mus musculus (house mouse)
Recombinant expressionOrganism: Homo sapiens (human) / Recombinant cell: Expi293F

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Macromolecule #1: B-lymphocyte antigen CD19

MacromoleculeName: B-lymphocyte antigen CD19 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 36.031578 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DYKDDDDLEV LFQGPPEEPL VVKVEEGDNA VLQCLKGTSD GPTQQLTWSR ESPLKPFLKL SLGLPGLGIH MRPLAIWLFI FNVSQQMGG FYLCQPGPPS EKAWQPGWTV NVEGSGELFR WNVSDLGGLG CGLKNRSSEG PSSPSGKLMS PKLYVWAKDR P EIWEGEPP ...String:
DYKDDDDLEV LFQGPPEEPL VVKVEEGDNA VLQCLKGTSD GPTQQLTWSR ESPLKPFLKL SLGLPGLGIH MRPLAIWLFI FNVSQQMGG FYLCQPGPPS EKAWQPGWTV NVEGSGELFR WNVSDLGGLG CGLKNRSSEG PSSPSGKLMS PKLYVWAKDR P EIWEGEPP CLPPRDSLNQ SLSQDLTMAP GSTLWLSCGV PPDSVSRGPL SWTHVHPKGP KSLLSLELKD DRPARDMWVM ET GLLLPRA TAQDAGKYYC HRGNLTMSFH LEITARPVLW HWLLRTGGWK VSAVTLAYLI FCLCSLVGIL HLQRALVLRR KRK RMT

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Macromolecule #2: CD81 antigen

MacromoleculeName: CD81 antigen / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 26.444758 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GGSGGSGGSG GSGVEGCTKC IKYLLFVFNF VFWLAGGVIL GVALWLRHDP QTTNLLYLEL GDKPAPNTFY VGIYILIAVG AVMMFVGFL GCYGAIQESQ CLLGTFFTCL VILFACEVAA GIWGFVNKDQ IAKDVKQFYD QALQQAVVDD DANNAKAVVK T FHETLDCC ...String:
GGSGGSGGSG GSGVEGCTKC IKYLLFVFNF VFWLAGGVIL GVALWLRHDP QTTNLLYLEL GDKPAPNTFY VGIYILIAVG AVMMFVGFL GCYGAIQESQ CLLGTFFTCL VILFACEVAA GIWGFVNKDQ IAKDVKQFYD QALQQAVVDD DANNAKAVVK T FHETLDCC GSSTLTALTT SVLTSNLCPS GSNIISNLFK EDCHQKIDDL FSGKLYLIGI AAIVVAVIMI FEMILSMVLC CG IRNSSVY

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Macromolecule #3: Coltuximab Heavy Chain

MacromoleculeName: Coltuximab Heavy Chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 24.828639 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QVQLVQPGAE VVKPGASVKL SCKTSGYTFT SNWMHWVKQA PGQGLEWIGE IDPSDSYTNY NQNFQGKAKL TVDKSTSTAY MEVSSLRSD DTAVYYCARG SNPYYYAMDY WGQGTSVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV S WNSGALTS ...String:
QVQLVQPGAE VVKPGASVKL SCKTSGYTFT SNWMHWVKQA PGQGLEWIGE IDPSDSYTNY NQNFQGKAKL TVDKSTSTAY MEVSSLRSD DTAVYYCARG SNPYYYAMDY WGQGTSVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV S WNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT QTYICNVNHK PSNTKVDKKV EPKSCGGSGL EVLFQ

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Macromolecule #4: Coltuximab Light Chain

MacromoleculeName: Coltuximab Light Chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
Molecular weightTheoretical: 23.211758 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: EIVLTQSPAI MSASPGERVT MTCSASSGVN YMHWYQQKPG TSPRRWIYDT SKLASGVPAR FSGSGSGTDY SLTISSMEPE DAATYYCHQ RGS(UNK)(UNK)YTFGG GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNA LQSGNS ...String:
EIVLTQSPAI MSASPGERVT MTCSASSGVN YMHWYQQKPG TSPRRWIYDT SKLASGVPAR FSGSGSGTDY SLTISSMEPE DAATYYCHQ RGS(UNK)(UNK)YTFGG GTKLEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNA LQSGNS QESVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC

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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

Concentration1.8 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
150.0 mMNaClsodium chloride
20.0 mMHEPES4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
0.05 %(w:v)GDNglyco-diosgenin
0.005 %(w:v)CHSCholesteryl hemisuccinate
GridModel: Quantifoil / Material: COPPER / Mesh: 400
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 295 K / Instrument: FEI VITROBOT MARK IV
Details: Blot for 4.5-5.5 seconds with a blot force of 15-16..

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Number grids imaged: 6 / Average electron dose: 55.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 2798945
CTF correctionSoftware - Name: CTFFIND (ver. 4)
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 244583
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 3.0.8)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. v2)

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Atomic model buiding 1

Initial model
PDB IDChain

6al5

chain_id: A

5tcx


6ani

chain_id: H

6ani

chain_id: L
Output model

PDB-7jic:
Structure of human CD19-CD81 co-receptor complex bound to coltuximab Fab fragment

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