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- PDB-8vse: Cryo-EM structure of human CD45 extracellular region in complex w... -

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Basic information

Entry
Database: PDB / ID: 8vse
TitleCryo-EM structure of human CD45 extracellular region in complex with adenoviral protein E3/49K
Components
  • 45.5kDa protein
  • Receptor-type tyrosine-protein phosphatase C
KeywordsIMMUNE SYSTEM / Complex / T cell signaling / Viral suppression
Function / homology
Function and homology information


plasma membrane raft distribution / positive regulation of antigen receptor-mediated signaling pathway / positive regulation of hematopoietic stem cell migration / negative regulation of cytokine-mediated signaling pathway / negative regulation of interleukin-4-mediated signaling pathway / alpha-beta T cell proliferation / positive regulation of Fc receptor mediated stimulatory signaling pathway / negative regulation of cell adhesion involved in substrate-bound cell migration / regulation of interleukin-8 production / regulation of T cell receptor signaling pathway ...plasma membrane raft distribution / positive regulation of antigen receptor-mediated signaling pathway / positive regulation of hematopoietic stem cell migration / negative regulation of cytokine-mediated signaling pathway / negative regulation of interleukin-4-mediated signaling pathway / alpha-beta T cell proliferation / positive regulation of Fc receptor mediated stimulatory signaling pathway / negative regulation of cell adhesion involved in substrate-bound cell migration / regulation of interleukin-8 production / regulation of T cell receptor signaling pathway / membrane microdomain / negative regulation of T cell mediated cytotoxicity / negative regulation of microglial cell activation / Other semaphorin interactions / positive regulation of humoral immune response mediated by circulating immunoglobulin / cell cycle phase transition / DN2 thymocyte differentiation / gamma-delta T cell differentiation / positive regulation of gamma-delta T cell differentiation / transmembrane receptor protein tyrosine phosphatase activity / natural killer cell differentiation / positive regulation of alpha-beta T cell proliferation / bleb / stem cell development / positive regulation of isotype switching to IgG isotypes / negative thymic T cell selection / negative regulation of receptor signaling pathway via JAK-STAT / regulation of phagocytosis / positive thymic T cell selection / heparan sulfate proteoglycan binding / protein tyrosine kinase inhibitor activity / positive regulation of extrinsic apoptotic signaling pathway / bone marrow development / heterotypic cell-cell adhesion / ankyrin binding / positive regulation of immunoglobulin production / negative regulation of interleukin-2 production / dephosphorylation / leukocyte cell-cell adhesion / spectrin binding / response to aldosterone / positive regulation of stem cell proliferation / Phosphorylation of CD3 and TCR zeta chains / B cell proliferation / T cell differentiation / positive regulation of protein kinase activity / hematopoietic progenitor cell differentiation / positive regulation of T cell proliferation / positive regulation of phagocytosis / protein dephosphorylation / extrinsic apoptotic signaling pathway / positive regulation of B cell proliferation / release of sequestered calcium ion into cytosol / protein tyrosine phosphatase activity / protein-tyrosine-phosphatase / protein tyrosine phosphatase activity, metal-dependent / histone H2AXY142 phosphatase activity / non-membrane spanning protein tyrosine phosphatase activity / positive regulation of interleukin-2 production / B cell differentiation / positive regulation of calcium-mediated signaling / T cell activation / secretory granule membrane / negative regulation of protein kinase activity / response to gamma radiation / B cell receptor signaling pathway / negative regulation of ERK1 and ERK2 cascade / positive regulation of T cell mediated cytotoxicity / cytoplasmic side of plasma membrane / positive regulation of tumor necrosis factor production / MAPK cascade / heparin binding / T cell receptor signaling pathway / regulation of gene expression / defense response to virus / cell surface receptor signaling pathway / positive regulation of ERK1 and ERK2 cascade / positive regulation of MAPK cascade / regulation of cell cycle / membrane raft / external side of plasma membrane / signaling receptor binding / focal adhesion / synapse / Neutrophil degranulation / protein kinase binding / negative regulation of transcription by RNA polymerase II / cell surface / signal transduction / extracellular exosome / membrane / plasma membrane
Similarity search - Function
Adenovirus E3 region protein CR2 / Adenovirus E3 region protein CR1 / Adenovirus E3 region protein CR2 / Adenovirus E3 region protein CR1 / Receptor-type tyrosine-protein phosphatase C / Protein tyrosine phosphatase, receptor type, N-terminal / Protein tyrosine phosphatase N terminal / Leukocyte receptor CD45 / : / Protein tyrosine phosphatase, catalytic domain ...Adenovirus E3 region protein CR2 / Adenovirus E3 region protein CR1 / Adenovirus E3 region protein CR2 / Adenovirus E3 region protein CR1 / Receptor-type tyrosine-protein phosphatase C / Protein tyrosine phosphatase, receptor type, N-terminal / Protein tyrosine phosphatase N terminal / Leukocyte receptor CD45 / : / Protein tyrosine phosphatase, catalytic domain / PTP type protein phosphatase domain profile. / Protein-tyrosine phosphatase / Tyrosine-specific protein phosphatase, PTPase domain / Protein-tyrosine phosphatase, catalytic / Protein tyrosine phosphatase, catalytic domain motif / Tyrosine specific protein phosphatases active site. / Protein-tyrosine phosphatase, active site / Tyrosine-specific protein phosphatases domain / Tyrosine specific protein phosphatases domain profile. / Protein-tyrosine phosphatase-like / Fibronectin type III domain / Fibronectin type 3 domain / Fibronectin type-III domain profile. / Fibronectin type III / Fibronectin type III superfamily / Immunoglobulin-like fold
Similarity search - Domain/homology
Receptor-type tyrosine-protein phosphatase C / 45.5kDa protein
Similarity search - Component
Biological speciesHomo sapiens (human)
Human adenovirus 19a
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsBorowska, M.T. / Caveney, N.A. / Jude, K.M. / Garcia, K.C.
Funding support United States, 3items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)RO1-AI103867 United States
Ludwig Institute for Cancer Research (LICR) United States
CitationJournal: Sci Immunol / Year: 2024
Title: Orientation-dependent CD45 inhibition with viral and engineered ligands.
Authors: Marta T Borowska / Liu D Liu / Nathanael A Caveney / Kevin M Jude / Won-Ju Kim / Takeya Masubuchi / Enfu Hui / Robbie G Majzner / K Christopher Garcia /
Abstract: CD45 is a cell surface phosphatase that shapes the T cell receptor signaling threshold but does not have a known ligand. A family of adenovirus proteins, including E3/49K, exploits CD45 to evade ...CD45 is a cell surface phosphatase that shapes the T cell receptor signaling threshold but does not have a known ligand. A family of adenovirus proteins, including E3/49K, exploits CD45 to evade immunity by binding to the extracellular domain of CD45, resulting in the suppression of T cell signaling. We determined the cryo-EM structure of this complex and found that the E3/49K protein is composed of three immunoglobulin domains assembled as "beads on a string" that compel CD45 into a closely abutted dimer by cross-linking the CD45 D3 domain, leading to steric inhibition of its intracellular phosphatase activity. Inspired by the E3/49K mechanism, we engineered CD45 surrogate ligands that can fine-tune T cell activation by dimerizing CD45 into different orientations and proximities. The adenovirus E3/49K protein has taught us that, despite a lack of a known ligand, CD45 activity can be modulated by extracellular dimerizing ligands that perturb its phosphatase activity and alter T cell responses.
History
DepositionJan 23, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 6, 2024Provider: repository / Type: Initial release
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Revision 1.1Nov 27, 2024Group: Data collection / Category: em_admin / Item: _em_admin.last_update
Revision 1.2May 21, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1May 21, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Receptor-type tyrosine-protein phosphatase C
B: Receptor-type tyrosine-protein phosphatase C
C: 45.5kDa protein
hetero molecules


Theoretical massNumber of molelcules
Total (without water)165,07615
Polymers160,8373
Non-polymers4,23912
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Receptor-type tyrosine-protein phosphatase C / Leukocyte common antigen / L-CA / T200


Mass: 60713.836 Da / Num. of mol.: 2 / Fragment: extracellular domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTPRC, CD45 / Production host: Homo sapiens (human) / References: UniProt: P08575, protein-tyrosine-phosphatase
#2: Protein 45.5kDa protein / E3 protein ( 49Kprotein )


Mass: 39408.938 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Human adenovirus 19a / Gene: 49K, E3 / Production host: Homo sapiens (human) / References: UniProt: Q67812
#3: Polysaccharide
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 6 / Source method: obtained synthetically
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#4: Polysaccharide beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta- ...beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 586.542 Da / Num. of mol.: 1 / Source method: obtained synthetically
DescriptorTypeProgram
DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/2,3,2/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5]/1-1-2/a4-b1_b4-c1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{}}}LINUCSPDB-CARE
#5: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
Has ligand of interestN
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 extracellular domain od human CD45 and extracellular domain of adenoviral protein E3/49K
Type: COMPLEX / Entity ID: #2 / Source: MULTIPLE SOURCES
Molecular weightValue: 0.164 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenConc.: 1.8 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: OTHER / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.3.1particle selection
4cryoSPARC4.3.1CTF correction
9PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 5306556
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 377081 / Symmetry type: POINT
Atomic model buildingProtocol: FLEXIBLE FIT / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0028251
ELECTRON MICROSCOPYf_angle_d0.49411204
ELECTRON MICROSCOPYf_dihedral_angle_d9.1973362
ELECTRON MICROSCOPYf_chiral_restr0.0431274
ELECTRON MICROSCOPYf_plane_restr0.0031430

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