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- EMDB-17220: Human Complement C3b in complex with Trypanosoma brucei ISG65 -

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Basic information

Entry
Database: EMDB / ID: EMD-17220
TitleHuman Complement C3b in complex with Trypanosoma brucei ISG65
Map dataHuman Complement C3b in complex with T. brucei ISG65. Local alignment of C3c region. Postprocessed in DeepEMhancer.
Sample
  • Complex: Human C3b in complex with Trypanosoma brucei ISG65
    • Complex: Complement C3b
    • Complex: Invariant surface glycoprotein 65Variant surface glycoprotein
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: 3.2 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
DepositionApr 26, 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_17220.png

Downloads & links

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Map

FileDownload / File: emd_17220.map.gz / Format: CCP4 / Size: 144.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHuman Complement C3b in complex with T. brucei ISG65. Local alignment of C3c region. Postprocessed in DeepEMhancer.
Projections & slices

Image control

Size
Brightness
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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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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.832 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.15
Minimum - Maximum-0.0018395517 - 1.8652701
Average (Standard dev.)0.0011186244 (±0.023340248)
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_17220_half_map_1.map
Projections & Slices
AxesZYX

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Density Histograms

Histogram

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Half map: #2

Fileemd_17220_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : Human C3b in complex with Trypanosoma brucei ISG65

EntireName: Human C3b in complex with Trypanosoma brucei ISG65
Components
  • Complex: Human C3b in complex with Trypanosoma brucei ISG65
    • Complex: Complement C3b
    • Complex: Invariant surface glycoprotein 65Variant surface glycoprotein

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Supramolecule #1: Human C3b in complex with Trypanosoma brucei ISG65

SupramoleculeName: Human C3b in complex with Trypanosoma brucei ISG65 / type: complex / ID: 1 / Parent: 0
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 44 KDa

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Supramolecule #2: Complement C3b

SupramoleculeName: Complement C3b / type: complex / ID: 2 / Parent: 1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #3: Invariant surface glycoprotein 65

SupramoleculeName: Invariant surface glycoprotein 65 / type: complex / ID: 3 / Parent: 1
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:
ConcentrationName
20.0 mMHEPES
150.0 mMNaClSodium chloride
0.01 %Fluorinated octyl maltoside
VitrificationCryogen name: ETHANE / Chamber humidity: 100 %

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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 / Nominal defocus max: 3.0 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 49.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 481606

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