Spain, European Union, Mexico, United Kingdom, 9 items
Organization
Grant number
Country
Ministerio de Ciencia e Innovacion (MCIN)
PID2023-149259NB-I00,
Spain
European Regional Development Fund
PID2023-149259NB-I00
European Union
Agencia Estatal de Investigacion (AEI)
PID2023-149259NB-I00
Spain
Consejo Nacional de Ciencia y Tecnologia (CONACYT)
773992
Mexico
Engineering and Physical Sciences Research Council
EP/W524372/1
United Kingdom
Wellcome Trust
220628/Z/20/Z
United Kingdom
Wellcome Trust
221524/Z/20/Z
United Kingdom
Wellcome Trust
223810/Z/21/Z
United Kingdom
Wolfson Foundation
PR/jw/md/22597
United Kingdom
Citation
Journal: bioRxiv / Year: 2025 Title: Unveiling the unique interaction mechanism of herpes simplex virus 2 glycoprotein C with C3b. Authors: Moisés Hasim Rojas Rechy / Doina Atanasiu / Lauren M Hook / Tina M Cairns / Wan Ting Saw / Adam Cahill / Zilin Guo / Antonio N Calabrese / Neil A Ranson / Harvey M Friedman / Gary H Cohen / Juan Fontana / Abstract: The complement cascade is part of the first line of defence against viral infections, and many viruses have evolved to block it. For example, glycoprotein C (gC) from Herpes Simplex Virus 1 and 2 ...The complement cascade is part of the first line of defence against viral infections, and many viruses have evolved to block it. For example, glycoprotein C (gC) from Herpes Simplex Virus 1 and 2 (gC1 and gC2) facilitates infection by modulating the complement cascade through an interaction with C3b. gC is also involved in attachment and other viral processes. However, our understanding of the molecular mechanisms of gC have been limited due to the absence of a structure. AlphaFold predicts that gC contains a disordered N-terminus and three immunoglobulin-like domains. Here, we generated various gC2 constructs and demonstrated that gC2 domains 1 and 2 are necessary and sufficient to interact with C3b and block the alternative pathway. A gC2 construct lacking the N-terminus in complex with C3b was characterised by cryo-EM at 3.6 Å, providing the first structure for gC2, and revealing that the interaction is predominantly driven by gC2 domain 2 and the MG8 domain of C3b. This structure was confirmed by cross-linking mass spectrometry and by using C3b-blocking antibodies that recognised gC2 linear epitopes at the interface with C3b. Overall, the gC-C3b interaction is different from other C3b-interacting partners, providing a novel mechanism to regulate the complement cascade.
Entire : Glycoprotein C of Herpes Simplex Virus, domains 1 and 2 with huma...
Entire
Name: Glycoprotein C of Herpes Simplex Virus, domains 1 and 2 with human complement protein C3b.
Components
Complex: Glycoprotein C of Herpes Simplex Virus, domains 1 and 2 with human complement protein C3b.
Complex: Herpes simplex virus 2, delta28-73 glycoprotein C ectodomain
Complex: Complement human protein C3b
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Supramolecule #1: Glycoprotein C of Herpes Simplex Virus, domains 1 and 2 with huma...
Supramolecule
Name: Glycoprotein C of Herpes Simplex Virus, domains 1 and 2 with human complement protein C3b. type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3 Details: Glycoprotein C has a deletion in the amino-acids 28-73
Source (natural)
Organism: Human alphaherpesvirus 2
Molecular weight
Theoretical: 180 KDa
-
Supramolecule #2: Herpes simplex virus 2, delta28-73 glycoprotein C ectodomain
Supramolecule
Name: Herpes simplex virus 2, delta28-73 glycoprotein C ectodomain type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1 / Details: gC2 has a deletion in the amino-acids 28-73
Source (natural)
Organism: Human alphaherpesvirus 2
-
Supramolecule #3: Complement human protein C3b
Supramolecule
Name: Complement human protein C3b / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2-#3 / Details: Chains A and B from complement protein C3b.
Source (natural)
Organism: Homo sapiens (human)
-
Experimental details
-
Structure determination
Method
cryo EM
Processing
single particle reconstruction
Aggregation state
particle
-
Sample preparation
Buffer
pH: 7.4
Vitrification
Cryogen name: ETHANE
-
Electron microscopy
Microscope
TFS KRIOS
Image recording
Film or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 46.0 e/Å2
Electron beam
Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
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