Key Points

  • aHUS-associated FHR-1 mutants are pathogenic because acquire capacity to bind sialic acids, which allows C3b-binding competition with FH.

  • The mechanism by which surface-bound FHR-1 promotes complement activation is the binding and attraction of native C3 to the cell surface.

Factor H-related proteins (FHRs) are a group of partly characterized complement proteins that are thought to promote complement activation by competing binding of factor H (FH) to surface-bound C3b. Among them, FHR-1 is remarkable because is associated with atypical hemolytic uremic syndrome (aHUS) and other important diseases. Using a combination of biochemical, immunological, nuclear magnetic resonance and computational approaches, we have characterized a series of FHR-1 mutants (including two associated with aHUS) and have unraveled the molecular bases of the so-called de-regulation activity of FHR-1. In contrast with FH, FHR-1 lacks the capacity to bind sialic acids, which prevents C3b-binding competition between FH and FHR-1 in host cell surfaces. aHUS-associated FHR-1 mutants are pathogenic because they have acquired the capacity to bind sialic acids, which increases FHR-1 avidity for surface-bound C3-activated fragments and results in C3b-binding competition with FH. FHR-1 binds to native C3, in addition to C3b, iC3b and C3dg. This unexpected finding suggests that the mechanism by which surface-bound FHR-1 promotes complement activation is the attraction of native C3 to the cell surface. Whilst C3b-binding competition with FH is limited to aHUS-associated mutants, all surface-bound FHR-1 promote complement activation, which is delimited by the FHR-1/FH activity ratio. Our data indicate that the FHR-1 de-regulation activity is important to sustain complement activation and C3 deposition at complement activating surfaces. They also support that abnormally elevated FHR-1/FH activity ratios would perpetuate a pathological complement dysregulation at complement activating surfaces, which may explain the association of FHR-1 quantitative variations with diseases.

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