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ORIGINAL RESEARCH article

Front. Hematol.
Sec. Immunobiology and Immunotherapy
Volume 3 - 2024 | doi: 10.3389/frhem.2024.1469176

Unique target binding by the C-terminal Region of FHR1 provides a new perception of aHUS Pathology

Provisionally accepted
  • 1 Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany
  • 2 Applied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, Germany
  • 3 Colzyx AB, Sweden Medicon Village, Lund, Sweden
  • 4 Department of Cardiovascular Surgery, University Heart and Vascular Center, University Medical Center Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • 5 Section Nephropathology, University Hospital Eppendorf, Hamburg, Germany, Hamburg , Deutschland, Germany

The final, formatted version of the article will be published soon.

    FHR1 is a multifunctional human plasma protein with three C-terminal domains, namely short consensus repeats (SCR) 3-5, showing 98% sequence-identity with the complement inhibitor Factor H. We show that FHR1 uses all three C-terminal SCR to make surface contact. The conserved C-terminal regions of FHR1 and Factor H are altered in patients with atypicalhemolytic-uremic-syndrome. Therefore, we compared FHR1 isoforms with sequence-variations in SCR3, and pathogenic mutants with sequence variations in SCR5. Functional data revealed that residues YVQ vs HLE in SCR3 and LA vs SV in SCR5 altered ligand binding and surface interaction, influenced target recognition and complement control. Amino-acid-sequence variations in SCR3 influenced FHR1 contact with surface constituents, such as glycosaminoglycans. By contrast, SCR5, the most C-terminal domain, was more relevant for C3b/C3d contact. Notably, wild-type FHR1LA selected C3d, while pathogenic aHUS-associated alterations FHR1SV selected C3b. In consequence mutant FHR1SV altered fined-tuned FHR1directed effector functions while pathogenic Factor HLA modified C3-convertase control. This influences timing of complement control and inflammatory effector actions at modified selfsurfaces. Pathogenic FHR1SV, directed to C3b-decorated targets, adds inflammatory activity at a time when C3-convertase control is appropriate and conversely, mutant Factor HLA adds C3convertase control at C3d-coated surfaces when inflammatory effector functions are favorable. Further, our computational modelling approach confirms such distinct effects of FHR1 monomers and dimers as compared to flexible Factor H. These effects may explain inappropriate timing of complement regulation and inflammation of the aHUS-derived mutant proteins FHR1SV and Factor HLA.

    Keywords: complement, FHR1, Complement hemolysis, Hemolytic uremic syndrome, FHR1 Factor H balance at surfaces

    Received: 23 Jul 2024; Accepted: 07 Nov 2024.

    Copyright: © 2024 Zipfel, Perie, Stippa, Saffer, Hartmann, Matthias Mörglin, Zipfel, Figge, Wiech and Skerka. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Peter F. Zipfel, Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena, D- 07745, Germany

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