Dunne, OM, Gao, X, Nan, R, Gor, J, Adamson, PJ, Gordon, DL, Moulin, M, Haertlein, M, Forsyth, VT and Perkins, SJ (2021) A Dimerization Site at SCR-17/18 in Factor H Clarifies a New Mechanism for Complement Regulatory Control. Frontiers in Immunology, 11. 601895 - ?. ISSN 1664-3224

[thumbnail of A Dimerization Site at SCR-1718 in Factor H Clarifies a New Mechanism for Complement Regulatory Control.pdf]
A Dimerization Site at SCR-1718 in Factor H Clarifies a New Mechanism for Complement Regulatory Control.pdf - Published Version
Available under License Creative Commons Attribution.

Download (7MB) | Preview


Complement Factor H (CFH), with 20 short complement regulator (SCR) domains, regulates the alternative pathway of complement in part through the interaction of its C-terminal SCR-19 and SCR-20 domains with host cell-bound C3b and anionic oligosaccharides. In solution, CFH forms small amounts of oligomers, with one of its self-association sites being in the SCR-16/20 domains. In order to correlate CFH function with dimer formation and the occurrence of rare disease-associated variants in SCR-16/20, we identified the dimerization site in SCR-16/20. For this, we expressed, in Pichia pastoris, the five domains in SCR-16/20 and six fragments of this with one-three domains (SCR-19/20, SCR-18/20, SCR-17/18, SCR-16/18, SCR-17 and SCR-18). Size-exclusion chromatography suggested that SCR dimer formation occurred in several fragments. Dimer formation was clarified using analytical ultracentrifugation, where quantitative c(s) size distribution analyses showed that SCR-19/20 was monomeric, SCR-18/20 was slightly dimeric, SCR-16/20, SCR-16/18 and SCR-18 showed more dimer formation, and SCR-17 and SCR-17/18 were primarily dimeric with dissociation constants of ~5 µM. The combination of these results located the SCR-16/20 dimerization site at SCR-17 and SCR-18. X-ray solution scattering experiments and molecular modelling fits confirmed the dimer site to be at SCR-17/18, this dimer being a side-by-side association of the two domains. We propose that the self-association of CFH at SCR-17/18 enables higher concentrations of CFH to be achieved when SCR-19/20 are bound to host cell surfaces in order to protect these better during inflammation. Dimer formation at SCR-17/18 clarified the association of genetic variants throughout SCR-16/20 with renal disease.

Item Type: Article
Additional Information: This is the final published version (version of record). It was first published online via Frontiers Media at https://doi.org/10.3389/fimmu.2020.601895 - please refer to any applicable terms of use of the publisher.
Uncontrolled Keywords: X-ray scattering, analytical ultracentrifugation, complement factor H, inflammation, molecular modelling
Subjects: Q Science > QR Microbiology
Divisions: Faculty of Natural Sciences > School of Life Sciences
Related URLs:
Depositing User: Symplectic
Date Deposited: 26 Feb 2021 11:05
Last Modified: 26 Feb 2021 11:09
URI: https://eprints.keele.ac.uk/id/eprint/9189

Actions (login required)

View Item
View Item