Associative and Structural Properties of the Region of Complement Factor H Encompassing the Tyr402His Disease-related Polymorphism and its Interactions with Heparin

Anira N. Fernando, Patricia B. Furtado, Simon J. Clark, Hannah E. Gilbert, Anthony J. Day, Robert B. Sim, Stephen J. Perkins

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Factor H (FH) is a major complement control protein in serum. The seventh short complement regulator (SCR-7) domain of the 20 in FH is associated with age-related macular degeneration through a Tyr402His polymorphism. The recombinant SCR-6/8 domains containing either His402 or Tyr402 and their complexes with a heparin decasaccharide were studied by analytical ultracentrifugation and X-ray scattering. The sedimentation coefficient is concentration dependent, giving a value of 2.0 S at zero concentration and a frictional ratio f/fo of 1.2 for both allotypes. The His402 allotype showed a slightly greater self-association than the Tyr402 allotype, and small amounts of dimeric SCR-6/8 were found for both allotypes in 50 mM, 137 mM and 250 mM NaCl buffers. Sedimentation equilibrium data were interpreted in terms of a monomer-dimer equilibrium with a dissociation constant of 40 μM for the His402 form. The Guinier radius of gyration RG of 3.1-3.3 nm and the RG/RO ratio of 2.0-2.1 showed that SCR-6/8 is relatively extended in solution. The distance distribution function P(r) showed a maximum dimension of 10 nm, which is less than the length expected for a linear domain arrangement. The constrained scattering and sedimentation modelling of FH SCR-6/8 showed that bent SCR arrangements fit the data better than linear arrangements. Previously identified heparin-binding residues were exposed on the outside curvature of this bent domain structure. Heparin caused the formation of a more linear structure, possibly by binding to residues in the linker. It was concluded that the His402 allotype may self-associate more readily than the Tyr402 allotype, SCR-6/8 is partly responsible for the folded-back structure of intact FH, and SCR-6/8 changes conformation upon heparin binding. © 2007 Elsevier Ltd. All rights reserved.
    Original languageEnglish
    Pages (from-to)564-581
    Number of pages17
    JournalJournal of molecular biology
    Volume368
    Issue number2
    DOIs
    Publication statusPublished - 27 Apr 2007

    Keywords

    • factor H
    • homology modelling
    • ultracentrifugation
    • X-ray scattering

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