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- EMDB-17209: Human Complement C3b in complex with Trypanosoma brucei ISG65. -

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Basic information

Entry
Database: EMDB / ID: EMD-17209
TitleHuman Complement C3b in complex with Trypanosoma brucei ISG65.
Map dataHuman Complement C3 in complex with T. brucei ISG65. Composite map from local alignments of the CUB-TED-ISG65 and remaining C3b regions. Postprocessed in DeepEMhancer.Complement component 3
Sample
  • Complex: Complex of Human Complement C3b and T. brucei ISG65
    • Complex: Human Complement C3b
      • Protein or peptide: Complement C3f fragment
      • Protein or peptide: Complement C3Complement component 3
    • Complex: Trypanosoma brucei ISG65
      • Protein or peptide: ISG65 G
KeywordsComplement system / parasite virulence / trypanosome surface protein / host-pathogen complex / IMMUNE SYSTEM
Function / homology
Function and homology information


oviduct epithelium development / C5L2 anaphylatoxin chemotactic receptor binding / regulation of triglyceride biosynthetic process / positive regulation of activation of membrane attack complex / vertebrate eye-specific patterning / positive regulation of apoptotic cell clearance / complement-mediated synapse pruning / Alternative complement activation / positive regulation of lipid storage / positive regulation of G protein-coupled receptor signaling pathway ...oviduct epithelium development / C5L2 anaphylatoxin chemotactic receptor binding / regulation of triglyceride biosynthetic process / positive regulation of activation of membrane attack complex / vertebrate eye-specific patterning / positive regulation of apoptotic cell clearance / complement-mediated synapse pruning / Alternative complement activation / positive regulation of lipid storage / positive regulation of G protein-coupled receptor signaling pathway / positive regulation of phagocytosis, engulfment / complement receptor mediated signaling pathway / Activation of C3 and C5 / positive regulation of type IIa hypersensitivity / positive regulation of glucose transmembrane transport / complement-dependent cytotoxicity / complement activation, alternative pathway / complement activation / neuron remodeling / endopeptidase inhibitor activity / amyloid-beta clearance / positive regulation of vascular endothelial growth factor production / Purinergic signaling in leishmaniasis infection / complement activation, classical pathway / Peptide ligand-binding receptors / fatty acid metabolic process / Regulation of Complement cascade / response to bacterium / Post-translational protein phosphorylation / positive regulation of receptor-mediated endocytosis / positive regulation of angiogenesis / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / azurophil granule lumen / Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell / G alpha (i) signalling events / secretory granule lumen / blood microparticle / immune response / inflammatory response / positive regulation of protein phosphorylation / G protein-coupled receptor signaling pathway / endoplasmic reticulum lumen / signaling receptor binding / Neutrophil degranulation / cell surface / signal transduction / protein-containing complex / extracellular space / extracellular exosome / extracellular region / membrane / plasma membrane
Similarity search - Function
Trypanosome invariant surface glycoprotein / Invariant surface glycoprotein / : / : / Complement component 3, CUB domain 2 / Complement component 3, CUB domain 1 / Complement C3-like, NTR domain / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. / Complement C3/4/5, macroglobulin domain MG1 ...Trypanosome invariant surface glycoprotein / Invariant surface glycoprotein / : / : / Complement component 3, CUB domain 2 / Complement component 3, CUB domain 1 / Complement C3-like, NTR domain / Alpha-2-macroglobulin, conserved site / Alpha-2-macroglobulin family thiolester region signature. / Complement C3/4/5, macroglobulin domain MG1 / Macroglobulin domain MG1 / : / Alpha-macro-globulin thiol-ester bond-forming region / Anaphylatoxin, complement system domain / Anaphylatoxin domain signature. / Anaphylatoxin/fibulin / Anaphylatoxin, complement system / Anaphylotoxin-like domain / Anaphylatoxin domain profile. / Anaphylatoxin homologous domain / Netrin C-terminal Domain / Netrin module, non-TIMP type / UNC-6/NTR/C345C module / Alpha-macroglobulin, receptor-binding / Alpha-macroglobulin, receptor-binding domain superfamily / Macroglobulin domain MG4 / Macroglobulin domain MG3 / A-macroglobulin receptor binding domain / Macroglobulin domain MG4 / Macroglobulin domain MG3 / A-macroglobulin receptor / Netrin domain / NTR domain profile. / Tissue inhibitor of metalloproteinases-like, OB-fold / Alpha-2-macroglobulin / Macroglobulin domain / Alpha-2-macroglobulin, bait region domain / Alpha-macroglobulin-like, TED domain / Alpha-2-macroglobulin family / MG2 domain / A-macroglobulin TED domain / Alpha-2-macroglobulin bait region domain / Alpha-2-Macroglobulin / Alpha-2-macroglobulin family / Terpenoid cyclases/protein prenyltransferase alpha-alpha toroid / Immunoglobulin-like fold
Similarity search - Domain/homology
ISG65 G / Complement C3
Similarity search - Component
Biological speciesHomo sapiens (human) / Trypanosoma brucei brucei (eukaryote)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.4 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 25, 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_17209.png

Downloads & links

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Map

FileDownload / File: emd_17209.map.gz / Format: CCP4 / Size: 144.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationHuman Complement C3 in complex with T. brucei ISG65. Composite map from local alignments of the CUB-TED-ISG65 and remaining C3b regions. Postprocessed in DeepEMhancer.
Projections & slices

Image control

Size
Brightness
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

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

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 - 1.873865
Average (Standard dev.)0.0015222499 (±0.027328268)
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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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
      • Protein or peptide: Complement C3f fragment
      • Protein or peptide: Complement C3Complement component 3
    • Complex: Trypanosoma brucei ISG65
      • Protein or peptide: ISG65 G

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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: all
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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Macromolecule #1: Complement C3f fragment

MacromoleculeName: Complement C3f fragment / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human) / Tissue: Blood
Molecular weightTheoretical: 71.154047 KDa
SequenceString: SPMYSIITPN ILRLESEETM VLEAHDAQGD VPVTVTVHDF PGKKLVLSSE KTVLTPATNH MGNVTFTIPA NREFKSEKGR NKFVTVQAT FGTQVVEKVV LVSLQSGYLF IQTDKTIYTP GSTVLYRIFT VNHKLLPVGR TVMVNIENPE GIPVKQDSLS S QNQLGVLP ...String:
SPMYSIITPN ILRLESEETM VLEAHDAQGD VPVTVTVHDF PGKKLVLSSE KTVLTPATNH MGNVTFTIPA NREFKSEKGR NKFVTVQAT FGTQVVEKVV LVSLQSGYLF IQTDKTIYTP GSTVLYRIFT VNHKLLPVGR TVMVNIENPE GIPVKQDSLS S QNQLGVLP LSWDIPELVN MGQWKIRAYY ENSPQQVFST EFEVKEYVLP SFEVIVEPTE KFYYIYNEKG LEVTITARFL YG KKVEGTA FVIFGIQDGE QRISLPESLK RIPIEDGSGE VVLSRKVLLD GVQNPRAEDL VGKSLYVSAT VILHSGSDMV QAE RSGIPI VTSPYQIHFT KTPKYFKPGM PFDLMVFVTN PDGSPAYRVP VAVQGEDTVQ SLTQGDGVAK LSINTHPSQK PLSI TVRTK KQELSEAEQA TRTMQALPYS TVGNSNNYLH LSVLRTELRP GETLNVNFLL RMDRAHEAKI RYYTYLIMNK GRLLK AGRQ VREPGQDLVV LPLSITTDFI PSFRLVAYYT LIGASGQREV VADSVWVDVK DSCVGSLVVK SGQSEDRQPV PGQQMT LKI EGDHGARVVL VAVDKGVFVL NKKNKLTQSK IWDVVEKADI GCTPGSGKDY AGVFSDAGLT FTSSSGQQTA QRAELQC PQ

UniProtKB: Complement C3

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Macromolecule #2: Complement C3

MacromoleculeName: Complement C3 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human) / Tissue: Blood
Molecular weightTheoretical: 104.073164 KDa
SequenceString: SNLDEDIIAE ENIVSRSEFP ESWLWNVEDL KEPPKNGIST KLMNIFLKDS ITTWEILAVS MSDKKGICVA DPFEVTVMQD FFIDLRLPY SVVRNEQVEI RAVLYNYRQN QELKVRVELL HNPAFCSLAT TKRRHQQTVT IPPKSSLSVP YVIVPLKTGL Q EVEVKAAV ...String:
SNLDEDIIAE ENIVSRSEFP ESWLWNVEDL KEPPKNGIST KLMNIFLKDS ITTWEILAVS MSDKKGICVA DPFEVTVMQD FFIDLRLPY SVVRNEQVEI RAVLYNYRQN QELKVRVELL HNPAFCSLAT TKRRHQQTVT IPPKSSLSVP YVIVPLKTGL Q EVEVKAAV YHHFISDGVR KSLKVVPEGI RMNKTVAVRT LDPERLGREG VQKEDIPPAD LSDQVPDTES ETRILLQGTP VA QMTEDAV DAERLKHLIV TPSGCGEQNM IGMTPTVIAV HYLDETEQWE KFGLEKRQGA LELIKKGYTQ QLAFRQPSSA FAA FVKRAP STWLTAYVVK VFSLAVNLIA IDSQVLCGAV KWLILEKQKP DGVFQEDAPV IHQEMIGGLR NNNEKDMALT AFVL ISLQE AKDICEEQVN SLPGSITKAG DFLEANYMNL QRSYTVAIAG YALAQMGRLK GPLLNKFLTT AKDKNRWEDP GKQLY NVEA TSYALLALLQ LKDFDFVPPV VRWLNEQRYY GGGYGSTQAT FMVFQALAQY QKDAPDHQEL NLDVSLQLPS RSSKIT HRI HWESASLLRS EETKENEGFT VTAEGKGQGT LSVVTMYHAK AKDQLTCNKF DLKVTIKPAP ETEKRPQDAK NTMILEI CT RYRGDQDATM SILDISMMTG FAPDTDDLKQ LANGVDRYIS KYELDKAFSD RNTLIIYLDK VSHSEDDCLA FKVHQYFN V ELIQPGAVKV YAYYNLEESC TRFYHPEKED GKLNKLCRDE LCRCAEENCF IQKSDDKVTL EERLDKACEP GVDYVYKTR LVKVQLSNDF DEYIMAIEQT IKSGSDEVQV GQQRTFISPI KCREALKLEE KKHYLMWGLS SDFWGEKPNL SYIIGKDTWV EHWPEEDEC QDEENQKQCQ DLGAFTESMV VFGCPN

UniProtKB: Complement C3

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Macromolecule #3: ISG65 G

MacromoleculeName: ISG65 G / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Trypanosoma brucei brucei (eukaryote)
Molecular weightTheoretical: 32.597322 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: DNRVPGDKNL TKEGAAALCK MKHLADKVAE KRSQELKDRT QNFAGYIEFE LYRIDYWLEK LNGPKGRKDG YAKLSDSDIE KVKEIFDKA KDGIAKQLPE AKKAGEDAEK LHTEVKEAAA NARGQDLDDH KQKSTGLYRV LNWYCITKEE SHNATPNCDG I QFRNHYLS ...String:
DNRVPGDKNL TKEGAAALCK MKHLADKVAE KRSQELKDRT QNFAGYIEFE LYRIDYWLEK LNGPKGRKDG YAKLSDSDIE KVKEIFDKA KDGIAKQLPE AKKAGEDAEK LHTEVKEAAA NARGQDLDDH KQKSTGLYRV LNWYCITKEE SHNATPNCDG I QFRNHYLS VNRSAIDCSS TGYEENYDWS ANALQVALNS WENVKPKKLE SAGSDENCNI GQSSESHPCT MTEEWQTHYK ET VKKLKEL EGAHEKGRRA HDAMLGYANT AYAVNTKVEQ EKPLAEVIAA AK

UniProtKB: ISG65 G

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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 / Material: GOLD / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 60 sec. / Pretreatment - Atmosphere: AIR
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: 3.4 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
Output model

PDB-8ovb:
Human Complement C3b in complex with Trypanosoma brucei ISG65.

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