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- PDB-7jic: Structure of human CD19-CD81 co-receptor complex bound to coltuxi... -

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Basic information

Entry
Database: PDB / ID: 7jic
TitleStructure of human CD19-CD81 co-receptor complex bound to coltuximab Fab fragment
Components
  • B-lymphocyte antigen CD19
  • CD81 antigen
  • Coltuximab Heavy Chain
  • Coltuximab Light Chain
KeywordsIMMUNE SYSTEM / tetraspanin / Fab / complex
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 / immunological synapse formation / tetraspanin-enriched microdomain / transferrin receptor binding / positive regulation of T-helper 2 cell cytokine production / protein localization to lysosome / B cell proliferation involved in immune response / positive regulation of protein exit from endoplasmic reticulum / MHC class II protein binding / positive regulation of CD4-positive, alpha-beta T cell proliferation / humoral immune response mediated by circulating immunoglobulin / cholesterol binding / positive regulation of T cell receptor signaling pathway / cellular response to low-density lipoprotein particle stimulus / immunoglobulin mediated immune response / immunological synapse / 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 / virus receptor activity / PIP3 activates AKT signaling / MHC class II protein complex binding / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsSusa, K.J. / Rawson, S. / Kruse, A.C. / Blacklow, S.C.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL 147459 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R35 CA220340 United States
National Institutes of Health/Office of the DirectorDP5 OD021345 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, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 20, 2021Provider: repository / Type: Initial release

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Structure visualization

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Assembly

Deposited unit
A: B-lymphocyte antigen CD19
B: CD81 antigen
H: Coltuximab Heavy Chain
L: Coltuximab Light Chain


Theoretical massNumber of molelcules
Total (without water)110,5174
Polymers110,5174
Non-polymers00
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein B-lymphocyte antigen CD19 / B-lymphocyte surface antigen B4 / Differentiation antigen CD19 / T-cell surface antigen Leu-12


Mass: 36031.578 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD19 / Plasmid: pcDNA3.1 / Cell line (production host): Expi293F / Production host: Homo sapiens (human) / References: UniProt: P15391
#2: Protein CD81 antigen / 26 kDa cell surface protein TAPA-1 / Target of the antiproliferative antibody 1 / Tetraspanin-28 / Tspan-28


Mass: 26444.758 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CD81, TAPA1, TSPAN28 / Plasmid: pcDNA3.1 / Cell line (production host): Expi293F / Production host: Homo sapiens (human) / References: UniProt: P60033
#3: Antibody Coltuximab Heavy Chain


Mass: 24828.639 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Plasmid: pFUSE / Cell line (production host): Expi293F / Production host: Homo sapiens (human)
#4: Antibody Coltuximab Light Chain


Mass: 23211.758 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Plasmid: pd2610-v5 / Cell line (production host): Expi293F / Production host: Homo sapiens (human)

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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

Component
IDNameTypeEntity IDParent-IDSource
1Complex of B cell co-receptor CD19 bound to the tetraspanin CD81 and coltuximab Fab fragmentCOMPLEXall0MULTIPLE SOURCES
2B cell co-receptor CD19 bound to the tetraspanin CD81COMPLEX#1-#21RECOMBINANT
3coltuximab Fab fragmentCOMPLEX#3-#41RECOMBINANT
Molecular weightValue: 0.110 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDCell
12Homo sapiens (human)9606Expi293F
23Homo sapiens (human)9606Expi293F
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
1150 mMsodium chlorideNaClSodium chloride1
220 mM4-(2-hydroxyethyl)-1-piperazineethanesulfonic acidHEPES1
30.05 %(w:v)glyco-diosgeninGDN1
40.005 %(w:v)Cholesteryl hemisuccinateCHS1
SpecimenConc.: 1.8 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 295 K
Details: Blot for 4.5-5.5 seconds with a blot force of 15-16.

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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 FIELDBright-field microscopy / Nominal magnification: 105000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 55 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 6

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.18rc5_3822refinement
PHENIX1.18rc5_3822refinement
EM software
IDNameVersionCategory
1crYOLOparticle selection
4CTFFIND4CTF correction
10RELION3.0.8initial Euler assignment
11cryoSPARCv2final Euler assignment
12cryoSPARCv2classification
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2798945
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 244583 / Num. of class averages: 1 / Symmetry type: POINT
Atomic model building
IDPDB-IDPdb chain-ID 3D fitting-ID
16AL5

6al5

A1
25TCX

5tcx

1
36ANI

6ani

H1
46ANI

6ani

L1
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 114.72 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00186114
ELECTRON MICROSCOPYf_angle_d0.40638354
ELECTRON MICROSCOPYf_chiral_restr0.0379962
ELECTRON MICROSCOPYf_plane_restr0.00311076
ELECTRON MICROSCOPYf_dihedral_angle_d9.0643865

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