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PreprintCited by 4Complement system in diseasesProtein Structure and DynamicsBiomarkers in Disease Mechanisms

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Structural modelling of human complement FHR1 and two of its synthetic derivatives provides insight into their in-vivo functions

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Ruiz-Molina, Natalia, Parsons, Juliana, Decker, Eva L., Reski, Ralf·2022·Computational and Structural Biotechnology Journal
DOI 10.1101/2022.11.24.517849PMC PMC9957715

Preprint — published as 10.1016/j.csbj.2023.02.002 · Paper page

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Abstract

Human complement is the first line of defence against invading pathogens and is involved in tissue homeostasis. Complement-targeted therapies to treat several diseases caused by a dysregulated complement are highly desirable. Despite huge efforts invested in their development, only very few are currently available, and a deeper understanding of the numerous interactions and complement regulation mechanisms is indispensable. Two important complement regulators are human Factor H (FH) and Factor H-related protein 1 (FHR1). MFHR1 and MFHR13, two promising therapeutic candidates based on these regulators, combine the dimerization and C5-regulatory domains of FHR1 with the central C3-regulatory and cell surface-recognition domains of FH. Here, we used AlphaFold2 to model the structure of these two synthetic regulators. Moreover, we used AlphaFold-Multimer (AFM) to study possible interactions of C3 fragments and membrane attack complex (MAC) components C5, C7 and C9 in complex with FHR1, MFHR1, MFHR13 as well as the best-known MAC regulators vitronectin (Vn), clusterin and CD59, whose experimental structures remain undetermined. AFM successfully predicted the binding interfaces of FHR1 and the synthetic regulators with C3 fragments and suggested binding to C3. The models revealed structural differences in binding to these ligands through different interfaces. Additionally, AFM predictions of Vn, clusterin or CD59 with C7 or C9 agreed with previously published experimental results. Because the role of FHR1 as a MAC regulator has been controversial, we analysed possible interactions with C5, C7 and C9. AFM predicted interactions of FHR1 with proteins of the terminal complement complex (TCC) as indicated by experimental observations, and located the interfaces in FHR1 1-2 and FHR 4-5 . According to AFM predictions, FHR1 might partially block the C3b binding site in C5, inhibiting C5 activation, and block C5b-7 complex formation and C9 polymerization, with similar mechanisms of action as clusterin and vitronectin. Here, we generate hypotheses and provide the basis for the design of rational approaches to understand the molecular mechanism of MAC inhibition, which will facilitate the development of further complement therapeutics.

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Metadata

Authors
Ruiz-Molina, N., Parsons, J., Decker, E. L., & Reski, R.
Affiliations
University of Freiburg (DE)
ORCID
Venue
Computational and Structural Biotechnology Journal
Publisher
openRxiv
Published
2022-11-24
Volume
21
Pages
1473-1486
ISSN
2001-0370 (ISSN-L)
DOI
10.1101/2022.11.24.517849
PMC
PMC9957715
OpenAlex
W4319072248
Cited by
4
References
2
Citations by year
2025: 1 · 2024: 3
FWCI
0.44
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Computational and Structural Biotechnology Journal (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Deutsche Forschungsgemeinschaft (EXC‐2189)
  • German Network for Bioinformatics Infrastructure
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Immunology and Microbiology › Immunology › Biomarkers in Disease Mechanisms
Keywords
complement factor H, complement regulatory proteins, membrane attack complex, vitronectin, clusterin, CD59, complement therapeutics, protein-protein interaction, binding interface

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