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Insights Into the Structure-Function Relationships of Dimeric C3d Fragments

Lookup NU author(s): Dr Beth Gibson, Dr Thomas Hallam, Professor Claire Harris, Professor Kevin MarchbankORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© Copyright © 2021 Wahid, Dunphy, Macpherson, Gibson, Kulik, Whale, Back, Hallam, Alkhawaja, Martin, Meschede, Laabei, Lawson, Holers, Watts, Crennell, Harris, Marchbank and van den Elsen.Cleavage of C3 to C3a and C3b plays a central role in the generation of complement-mediated defences. Although the thioester-mediated surface deposition of C3b has been well-studied, fluid phase dimers of C3 fragments remain largely unexplored. Here we show C3 cleavage results in the spontaneous formation of C3b dimers and present the first X-ray crystal structure of a disulphide-linked human C3d dimer. Binding studies reveal these dimers are capable of crosslinking complement receptor 2 and preliminary cell-based analyses suggest they could modulate B cell activation to influence tolerogenic pathways. Altogether, insights into the physiologically-relevant functions of C3d(g) dimers gained from our findings will pave the way to enhancing our understanding surrounding the importance of complement in the fluid phase and could inform the design of novel therapies for immune system disorders in the future.

Publication metadata

Author(s): Wahid AA, Dunphy RW, Macpherson A, Gibson BG, Kulik L, Whale K, Back C, Hallam TM, Alkhawaja B, Martin RL, Meschede I, Laabei M, Lawson ADG, Holers VM, Watts AG, Crennell SJ, Harris CL, Marchbank KJ, van den Elsen JMH

Publication type: Article

Publication status: Published

Journal: Frontiers in Immunology

Year: 2021

Volume: 12

Print publication date: 01/08/2021

Online publication date: 09/08/2021

Acceptance date: 21/07/2021

Date deposited: 09/09/2021

ISSN (electronic): 1664-3224

Publisher: Frontiers Media S.A.


DOI: 10.3389/fimmu.2021.714055


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Funder referenceFunder name
Alexion Pharmaceuticals funded TH’s PhD studentship via Complement UK.
BG and KM were funded by a Northern Counties Kidney Research Grant
Biotechnology and Biological Sciences Research Council Follow On Fund BB/N022165/1.
CH was funded by Newcastle University.
KM also recognises the support from Kidney Research UK grant (RP-006-20270301).
RD was supported by a Medical Research Council GW4 Doctoral Training Partnership.