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Insights into the structure-function relationships of dimeric C3d fragments

DOI: 10.3389/fimmu.2021.714055 DOI Help

Authors: Ayla A. Wahid (University of Bath) , Rhys W. Dunphy (University of Bath) , Alex Macpherson (University of Bath; UCB Pharma) , Beth G. Gibson (Newcastle University) , Liudmila Kulik (University of Colorado) , Kevin Whale (UCB Pharma) , Catherine Back (University of Bath) , Thomas M. Hallam (Newcastle University) , Bayan Alkhawaja (University of Bath) , Rebecca L. Martin (University of Bath) , Ingrid Meschede (UCB Pharma) , Maisem Laabei (University of Bath) , Alastair D. G. Lawson (UCB Pharma) , V. Michael Holers (University of Colorado) , Andrew G. Watts (University of Bath) , Susan J. Crennell (University of Bath) , Claire L. Harris (Newcastle University) , Kevin J. Marchbank (Newcastle University) , Jean M. H. Van Den Elsen (University of Bath)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Frontiers In Immunology , VOL 12

State: Published (Approved)
Published: August 2021
Diamond Proposal Number(s): 17212

Open Access Open Access

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.

Journal Keywords: complement; B cell; tolerance; C3d dimers; X-ray crystal and molecular structure

Subject Areas: Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography

Added On: 06/12/2021 14:16

Documents:
fimmu-12-714055.pdf

Discipline Tags:

Health & Wellbeing Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)