The solution structure of the complement deregulator FHR5 reveals a compact dimer and provides new insights into CFHR5 nephropathy
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The human complement Factor H-related 5 protein (FHR5) antagonizes the main circulating
complement regulator Factor H, resulting in the deregulation of complement activation. FHR5
normally contains nine short complement regulator (SCR) domains, but a FHR5 mutant has been
identified with a duplicated N-terminal SCR-1/2 domain pair that causes CFHR5 nephropathy. To
understand how this duplication causes disease, we characterized the solution structure of
native FHR5 by analytical ultracentrifugation and small-angle X-ray scattering. Sedimentation
velocity and X-ray scattering indicated that FHR5 was dimeric, with a radius of gyration
(Rg)
of 5.5 ± 0.2 nm and a maximum protein length of 20 nm for its 18 domains. This result indicated
that FHR5 was even more compact than the main regulator Factor H, which showed an overall length
of 26-29 nm for its 20 SCR domains. Atomistic modeling for FHR5 generated a library of 250,000
physically realistic trial arrangements of SCR domains for scattering curve fits. Only compact
domain structures in this library fit well to the scattering data, and these structures readily
accommodated the extra SCR-1/2 domain pair present in CFHR5 nephropathy. This model indicated
that mutant FHR5 can form oligomers that possess additional binding sites for C3b in FHR5. We
conclude that the deregulation of complement regulation by the FHR5 mutant can be rationalized
by the enhanced binding of FHR5 oligomers to C3b deposited on host cell surfaces. Our FHR5
structures thus explained key features of the mechanism and pathology of CFHR5 nephropathy.
Keywords: FHR5; Monte Carlo simulations; analytical ultracentrifugation; atomistic modeling;
complement; molecular dynamics; molecular modeling; small-angle X-ray scattering (SAXS);
small-angle X-ray scattering analytical ultracentrifugation.
Reference
Kadkhodayi-Kholghi, N., Bhatt, J. S., Gor, J., McDermott, L. C., Gale, D. P., & Perkins, S. J. (2020). The solution structure of the complement deregulator FHR5 reveals a compact dimer and provides new insights into CFHR5 nephropathy. Journal of Biological Chemistry, 295(48), 16342-16358.
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