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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Molecular Innate Immunity
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1522651

Functional and structural characterization of mouse Factor H-related B protein unveils a novel dimerization domain shared by FHR-B and FH

Provisionally accepted
Adrián Martín-Ambrosio Doménech Adrián Martín-Ambrosio Doménech 1Silvia González Sanz Silvia González Sanz 1Bárbara Márquez Tirado Bárbara Márquez Tirado 2Lucía Juana López Lucía Juana López 1Elena Goicoechea De Jorge Elena Goicoechea De Jorge 2Santiago Rodriguez De Cordoba Santiago Rodriguez De Cordoba 1*Héctor Martín Merinero Héctor Martín Merinero 1
  • 1 Spanish National Research Council (CSIC), Madrid, Madrid, Spain
  • 2 Complutense University of Madrid, Madrid, Madrid, Spain

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

    Factor H-related proteins (FHRs) are found in mice, but their equivalence to human FHRs remains uncertain. This study identifies three FHRs in mouse plasma (FHR-B, FHR-C, and FHR-E) and focuses on characterizing FHR-B. Using purified plasma proteins and recombinant mutants, FHR-B was found to form dimers and bind strongly to C3, C3b, iC3b, and C3dg. It also competes with mouse Factor H (mFH) for binding to C3b-coated surfaces and disrupts mFH regulation in hemolysis assays with sheep and guinea pig erythrocytes. These functions are localized to the C-terminal region and are dependent on FHR-B dimerization. Dimerization occurs through the N-terminal region (SCR1-3), which differs from mFH SCR5-7 by only four amino acids and also shares significant homology with human FHR-3 and human FH SCR5-7. In contrast to FHR-1, AUC experiments indicate that FHR-B dimerization is pH-sensitive, reversible and that the monomers in the dimer present the same head to tail orientation. Mutant analyses revealed that mFH SCR5-7 also forms dimers, but less efficiently than FHR-B. Notably, substituting FHR-B Tyr162 (a key residue homologous to the disease-associated Tyr402 in human FH) for His reduces dimerization. We also found that a recombinant FHR-B with a duplicated dimerization domain formed stable dimers but lacked functional activity. Overall, FHR-B shows structural and functional similarities with various human FHRs, suggesting convergent evolution between mouse and human FHRs. Furthermore, this study reveals a novel dimerization domain shared by FHR-B and mouse FH and illustrates the importance of dimerization and monomer orientation in FHRs activity. It also underlines notable differences between human and mice FHRs that should be further explored before modeling FHR-associated human diseases in mice.

    Keywords: factor H, Factor H related proteins, complement, regulation, complement-related diseases, dimerization

    Received: 04 Nov 2024; Accepted: 09 Jan 2025.

    Copyright: © 2025 Martín-Ambrosio Doménech, González Sanz, Márquez Tirado, Juana López, Goicoechea De Jorge, Rodriguez De Cordoba and Martín Merinero. 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: Santiago Rodriguez De Cordoba, Spanish National Research Council (CSIC), Madrid, 28006, Madrid, Spain

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