Insights into the structure-function relationships of dimeric C3d fragments

Ayla Wahid, Rhys Dunphy, Alex Macpherson, Beth Gibson, Liudmila Kulik, K. Whale, Catherine Back, Thomas Hallam, Bayan Alkhawaja, Beccie Martin, Ingrid Meschede, Maisem Laabei, Alastair Lawson, V. Michael Holers, Andrew Watts, Susan Crennell, Claire Harris, Kevin Marchbank, Jean Van Den Elsen

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Abstract

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.
Original languageEnglish
Article number714055
JournalFrontiers in Immunology
Volume12
Early online date9 Aug 2021
DOIs
Publication statusPublished - 9 Aug 2021

Bibliographical note

Funding Information:
CH has recently received consultancy or SAB payments from Freeline Therapeutics, Q32 Bio Inc., Roche, GlaxoSmithKline and Gyroscope Therapeutics and has received research funding from Ra Pharmaceuticals; all funds were donated to Newcastle University. TH is funded by Alexion Pharmaceuticals. Authors AM, KW, IM, and AL are or were employed by UCB-Pharma and may hold shares and/or stock options.

Funding Information:
This research was supported by the Biotechnology and Biological Sciences Research Council Follow On Fund BB/N022165/1. AAW was sponsored by a PhD studentship granted by Raoul and Catherine Hughes and the University of Bath Alumni Fund. RD was supported by a Medical Research Council GW4 Doctoral Training Partnership. BG and KM were funded by a Northern Counties Kidney Research Grant and Alexion Pharmaceuticals funded TH’s PhD studentship via Complement UK. KM also recognises the support from Kidney Research UK grant (RP-006-20270301). CH was funded by Newcastle University.

Funding Information:
The authors would like to acknowledge the team at the Diamond Light Source synchrotron (Oxfordshire, UK) for access to the IO4 beamline and Gyles Cozier for his help with data collection. Shaun Reeksting from the Material and Chemical Characterisation Facility (MC2, University of Bath) is also thanked for his assistance with the mass spectrometry analyses and Alexandra Solovyova of Newcastle University protein and proteome analysis (NUPPA) facility for her help with AUC analyses. Phil Stanley from UCB Biopharma UK is thanked for helping with the statistical analysis of the flow cytometry data.

Publisher Copyright:
© Copyright © 2021 Wahid, Dunphy, Macpherson, Gibson, Kulik, Whale, Back, Hallam, Alkhawaja, Martin, Meschede, Laabei, Lawson, Holers, Watts, Crennell, Harris, Marchbank and van den Elsen.

Keywords

  • B cell
  • C3d dimers
  • X-ray crystal and molecular structure
  • complement
  • tolerance

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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