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- EMDB-43497: Cryo-EM structure of human CD45 extracellular region in complex w... -

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Basic information

Entry
Database: EMDB / ID: EMD-43497
TitleCryo-EM structure of human CD45 extracellular region in complex with adenoviral protein E3/49K
Map data
Sample
  • Complex: Complex of extracellular domain od human CD45 and extracellular domain of adenoviral protein E3/49K
    • Protein or peptide: 45.5kDa protein
  • Protein or peptide: Receptor-type tyrosine-protein phosphatase C
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
KeywordsComplex / T cell signaling / Viral suppression / IMMUNE SYSTEM
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 / Other semaphorin interactions / negative regulation of microglial cell activation / 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 / natural killer cell differentiation / transmembrane receptor protein tyrosine phosphatase activity / positive regulation of alpha-beta T cell proliferation / bleb / positive regulation of isotype switching to IgG isotypes / stem cell development / negative thymic T cell selection / negative regulation of receptor signaling pathway via JAK-STAT / positive thymic T cell selection / regulation of phagocytosis / protein tyrosine kinase inhibitor activity / heparan sulfate proteoglycan binding / positive regulation of extrinsic apoptotic signaling pathway / bone marrow development / heterotypic cell-cell adhesion / ankyrin binding / positive regulation of immunoglobulin production / leukocyte cell-cell adhesion / dephosphorylation / negative regulation of interleukin-2 production / 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 phagocytosis / positive regulation of T cell proliferation / protein dephosphorylation / extrinsic apoptotic signaling pathway / release of sequestered calcium ion into cytosol / positive regulation of B cell proliferation / protein tyrosine phosphatase activity / positive regulation of interleukin-2 production / protein-tyrosine-phosphatase / protein tyrosine phosphatase activity, metal-dependent / histone H2AXY142 phosphatase activity / non-membrane spanning protein tyrosine phosphatase activity / B cell differentiation / positive regulation of calcium-mediated signaling / secretory granule membrane / T cell activation / response to gamma radiation / negative regulation of protein kinase activity / 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 peptidyl-tyrosine phosphorylation / positive regulation of tumor necrosis factor production / MAPK cascade / T cell receptor signaling pathway / heparin binding / regulation of gene expression / defense response to virus / positive regulation of MAPK cascade / positive regulation of ERK1 and ERK2 cascade / cell surface receptor signaling pathway / 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
Methodsingle particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsBorowska MT / Caveney NA / Jude KM / Garcia KC
Funding support United States, 3 items
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, 2024-
Header (metadata) releaseNov 6, 2024-
Map releaseNov 6, 2024-
UpdateNov 27, 2024-
Current statusNov 27, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43497.png

Downloads & links

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Map

FileDownload / File: emd_43497.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.2 Å/pix.
x 288 pix.
= 345.696 Å		1.2 Å/pix.
x 288 pix.
= 345.696 Å		1.2 Å/pix.
x 288 pix.
= 345.696 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.20033 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.296046 - 0.8287271
Average (Standard dev.)-0.0004243445 (±0.014643858)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 345.69598 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: #1

Fileemd_43497_additional_1.map
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Half map: #2

Fileemd_43497_half_map_1.map
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Half map: #1

Fileemd_43497_half_map_2.map
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Sample components

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Entire : Complex of extracellular domain od human CD45 and extracellular d...

EntireName: Complex of extracellular domain od human CD45 and extracellular domain of adenoviral protein E3/49K
Components
  • Complex: Complex of extracellular domain od human CD45 and extracellular domain of adenoviral protein E3/49K
    • Protein or peptide: 45.5kDa protein
  • Protein or peptide: Receptor-type tyrosine-protein phosphatase C
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: Complex of extracellular domain od human CD45 and extracellular d...

SupramoleculeName: Complex of extracellular domain od human CD45 and extracellular domain of adenoviral protein E3/49K
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 164 KDa

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Macromolecule #1: Receptor-type tyrosine-protein phosphatase C

MacromoleculeName: Receptor-type tyrosine-protein phosphatase C / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO / EC number: protein-tyrosine-phosphatase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 60.713836 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: QSPTPSPTGL TTAKMPSVPL SSDPLPTHTT AFSPASTFER ENDFSETTTS LSPDNTSTQV SPDSLDNASA FNTTGVSSVQ TPHLPTHAD SQTPSAGTDT QTFSGSAANA KLNPTPGSNA ISDVPGERST ASTFPTDPVS PLTTTLSLAH HSSAALPART S NTTITANT ...String:
QSPTPSPTGL TTAKMPSVPL SSDPLPTHTT AFSPASTFER ENDFSETTTS LSPDNTSTQV SPDSLDNASA FNTTGVSSVQ TPHLPTHAD SQTPSAGTDT QTFSGSAANA KLNPTPGSNA ISDVPGERST ASTFPTDPVS PLTTTLSLAH HSSAALPART S NTTITANT SDAYLNASET TTLSPSGSAV ISTTTIATTP SKPTCDEKYA NITVDYLYNK ETKLFTAKLN VNENVECGNN TC TNNEVHN LTECKNASVS ISHNSCTAPD KTLILDVPPG VEKFQLHDCT QVEKADTTIC LKWKNIETFT CDTQNITYRF QCG NMIFDN KEIKLENLEP EHEYKCDSEI LYNNHKFTNA SKIIKTDFGS PGEPQIIFCR SEAAHQGVIT WNPPQRSFHN FTLC YIKET EKDCLNLDKN LIKYDLQNLK PYTKYVLSLH AYIIAKVQRN GSAAMCHFTT KSAPPSQVWN MTVSMTSDNS MHVKC RPPR DRNGPHERYH LEVEAGNTLV RNESHKNCDF RVKDLQYSTD YTFKAYFHNG DYPGEPFILH HSTSYNS

UniProtKB: Receptor-type tyrosine-protein phosphatase C

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Macromolecule #2: 45.5kDa protein

MacromoleculeName: 45.5kDa protein / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Human adenovirus 19a
Molecular weightTheoretical: 39.408938 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GFHTINATWW ANITLVGPPD TPVTWYDTQG LWFCNGSRVK NPQIRHTCND QNLTLIHVNK TYERTYMGYN RQGTKKEDYK VVVIPPPPA TVKPQPEPEY VFVYMGENKT LEGPPGTPVT WFNQDGKKFC EGEKVLHPEF NHTCDKQNLI LLFVNFTHDG A YLGYNHQG ...String:
GFHTINATWW ANITLVGPPD TPVTWYDTQG LWFCNGSRVK NPQIRHTCND QNLTLIHVNK TYERTYMGYN RQGTKKEDYK VVVIPPPPA TVKPQPEPEY VFVYMGENKT LEGPPGTPVT WFNQDGKKFC EGEKVLHPEF NHTCDKQNLI LLFVNFTHDG A YLGYNHQG TQRTHYEVTV LDLFPDSGQM KIENHSEETE QKNDEHHNWQ KQGGQKQGGQ KTNQTKVNDR RKTAQKRPSK LK PATIEAM LVTVTAGSNL TLVGPKAEGK VTWFDGDLKR PCEPNYRLRH ECNNQNLTLI NVTKDYEGTY YGTNDKDEGK RYR VKVNTT NSQSVKIQGA PHHHHHH

UniProtKB: 45.5kDa protein

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 5 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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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
GridModel: Quantifoil R1.2/1.3 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k 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: OTHER / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 5306556
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

5mfv

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 377081
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER
FSC plot (resolution estimation)

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Atomic model buiding 1

RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-8vse:
Cryo-EM structure of human CD45 extracellular region in complex with adenoviral protein E3/49K

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