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- EMDB-17273: Structure of complement C3 bound to Trypanosoma brucei ISG65 -

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Basic information

Entry
Database: EMDB / ID: EMD-17273
TitleStructure of complement C3 bound to Trypanosoma brucei ISG65
Map data
Sample
  • Complex: Complex of Human Complement C3b and T. brucei ISG65
    • Complex: Human Complement C3b
    • Complex: Trypanosoma brucei ISG65
KeywordsComplement system / parasite virulence / trypanosome surface protein / host-pathogen complex / IMMUNE SYSTEM
Biological speciesHomo sapiens (human) / Trypanosoma brucei brucei (eukaryote)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsCook AD / Higgins MK
Funding support United Kingdom, 1 items
OrganizationGrant numberCountry
Wellcome Trust217138/Z/19/Z United Kingdom
CitationJournal: Elife / Year: 2024
Title: Molecular mechanism of complement inhibition by the trypanosome receptor ISG65.
Authors: Alexander D Cook / Mark Carrington / Matthew K Higgins /
Abstract: African trypanosomes replicate within infected mammals where they are exposed to the complement system. This system centres around complement C3, which is present in a soluble form in serum but ...African trypanosomes replicate within infected mammals where they are exposed to the complement system. This system centres around complement C3, which is present in a soluble form in serum but becomes covalently deposited onto the surfaces of pathogens after proteolytic cleavage to C3b. Membrane-associated C3b triggers different complement-mediated effectors which promote pathogen clearance. To counter complement-mediated clearance, African trypanosomes have a cell surface receptor, ISG65, which binds to C3b and which decreases the rate of trypanosome clearance in an infection model. However, the mechanism by which ISG65 reduces C3b function has not been determined. We reveal through cryogenic electron microscopy that ISG65 has two distinct binding sites for C3b, only one of which is available in C3 and C3d. We show that ISG65 does not block the formation of C3b or the function of the C3 convertase which catalyses the surface deposition of C3b. However, we show that ISG65 forms a specific conjugate with C3b, perhaps acting as a decoy. ISG65 also occludes the binding sites for complement receptors 2 and 3, which may disrupt recruitment of immune cells, including B cells, phagocytes, and granulocytes. This suggests that ISG65 protects trypanosomes by combining multiple approaches to dampen the complement cascade.
History
DepositionMay 3, 2023-
Header (metadata) releaseFeb 14, 2024-
Map releaseFeb 14, 2024-
UpdateMay 15, 2024-
Current statusMay 15, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_17273.png

Downloads & links

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Map

FileDownload / File: emd_17273.map.gz / Format: CCP4 / Size: 144.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 336 pix.
= 279.552 Å		0.83 Å/pix.
x 336 pix.
= 279.552 Å		0.83 Å/pix.
x 336 pix.
= 279.552 Å

Surface

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Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.832 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-0.023134038 - 1.8212236
Average (Standard dev.)0.0013067187 (±0.024490446)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions336336336
Spacing336336336
CellA=B=C: 279.552 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_17273_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_17273_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of Human Complement C3b and T. brucei ISG65

EntireName: Complex of Human Complement C3b and T. brucei ISG65
Components
  • Complex: Complex of Human Complement C3b and T. brucei ISG65
    • Complex: Human Complement C3b
    • Complex: Trypanosoma brucei ISG65

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Supramolecule #1: Complex of Human Complement C3b and T. brucei ISG65

SupramoleculeName: Complex of Human Complement C3b and T. brucei ISG65 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Source (natural)Organism: Homo sapiens (human) / Tissue: Blood
Molecular weightTheoretical: 44.2 KDa

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Supramolecule #2: Human Complement C3b

SupramoleculeName: Human Complement C3b / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1-#2
Details: C3 purified from human serum, C3b generated from C3 by limited trypsin proteolysis.
Source (natural)Organism: Homo sapiens (human) / Tissue: Blood

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Supramolecule #3: Trypanosoma brucei ISG65

SupramoleculeName: Trypanosoma brucei ISG65 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: Trypanosoma brucei brucei (eukaryote)

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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

Concentration2.2 mg/mL
BufferpH: 7.4
Component:
ConcentrationNameFormula
20.0 mMHEPES
150.0 mMSaltNaClSodium chloride
GridModel: Quantifoil R1.2/1.3 / Support film - Material: CARBON / Support film - topology: HOLEY
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 278.15 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Cs: 2.7 mm / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.0 µm
Specialist opticsEnergy filter - Name: GIF Quantum LS / Energy filter - Slit width: 20 eV
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 14339 / Average exposure time: 3.03 sec. / Average electron dose: 49.9 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 3824878
Startup modelType of model: INSILICO MODEL / In silico model: CryoSPARC Ab initio model
Initial angle assignmentType: PROJECTION MATCHING / Software: (Name: SIMPLE (ver. 3), cryoSPARC (ver. 3))
Final 3D classificationNumber classes: 5 / Software - Name: cryoSPARC (ver. 3)
Final angle assignmentType: PROJECTION MATCHING / Software - Name: cryoSPARC
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3) / Number images used: 481606

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Atomic model buiding 1

Initial model
ChainPDB ID
source_name: AlphaFold, initial_model_type: in silico model
source_name: PDB, initial_model_type: experimental model

5fo7

RefinementSpace: REAL / Protocol: OTHER

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