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The solution structure of the complement deregulator FHR5 reveals a compact dimer and provides new insights into CFHR5 nephropathy

  • Nilufar Kadkhodayi-Kholghi
    ,
  • Jayesh S. Bhatt
    ,
  • Jayesh Gor
    ,
  • Lindsay McDermott
    ,
  • Daniel P. Gale
    ,
  • Stephen J. Perkins
  • University College London
Research Output: Contribution to journal Article Peer-review

Open access

Sustainable Development Goals

  • SDG 3 - Good Health and Well-being
    SDG 3 Good Health and Well

Abstract

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 Xray 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 modelling 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.

Publication Information

Output type

Research Output: Contribution to journal Article Peer-review

Original language

English

Pages from-to (Number of pages)

Pages 16342-16358

Journal (Volume, Issue Number)

Journal of Biological Chemistry (Volume 295)

Publication milestones

  • Accepted/In press - 06/09/2020
  • Published - 14/09/2020

Publication status

Published - 14/09/2020

ISSN

0021-9258

External Publication IDs

  • handle.net: 10547/624515
  • Scopus: 85097003003

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