POS-003 The three C-terminal domains of FHR1 influence complement activation and FHR1 cooperation with other complement regulators

Perie, Luce; Stippa, Selina; Hartmann, Andrea; Mihlan, Michael; Skerka, Christina; Wiech, Thorsten; Zipfel, Peter F.

doi:10.1016/j.ekir.2022.04.020

Cited by 2 publications

(2 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These differences might explain previous results where MFHR13 protected more efficiently C3b-opsonized sheep erythrocytes from convertase-independent C5 activation and MAC formation than FHR1 [13] , as MFHR13 (FHR1 1–2 :FH 1–4 :FH 13 :FH 19–20 ) would bind more efficiently to the sialic acid-rich surface of sheep erythrocytes, regulating MAC formation on the cell surface. Furthermore, FH binds more efficiently to heparin-C3b while FHR1 binds better to a heparin-C3d combination [73] . Although in none of our models Leu 290 or Ala 296 were identified as key residues in the binding interfaces of FHR1, the effect of these motifs (SV and LA, on FH and FHR1, resp.)…”

Section: Resultsmentioning

confidence: 95%

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

Ruiz-Molina

Parsons

Decker

et al. 2023

Computational and Structural Biotechnology Journal

View full text Add to dashboard Cite

Section: Resultsmentioning

confidence: 95%

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

Ruiz-Molina

Parsons

Decker

et al. 2023

Computational and Structural Biotechnology Journal

View full text Add to dashboard Cite

“…These differences might explain previous results where MFHR13 protected C3b-opsonized sheep erythrocytes from convertase-independent C5 activation and MAC formation more efficiently than FHR1 [13], as MFHR13 (FHR1 1-2 :FH 1-4 :FH 13 :FH 19-20 ) would bind more efficiently to the sialic acid-rich surface of sheep erythrocytes, regulating MAC formation on the cell surface. Furthermore, FH binds more efficiently to heparin-C3b while FHR1 binds better to a heparin-C3d combination [73]. Although in none of our models Leu 290 or Ala 296 were identified as key residues in the binding interfaces of FHR1, the effect of these motifs (SV and LA, on FH and FHR1, respectively) on the binding capacity to C3b/C3d, C5, C7 and C9 should be experimentally investigated, in order to validate the binding interfaces in FHR1 4-5 and to elucidate if the inability of FH to bind to C5, C7 and C9 depends on the sequence of FH 20 or on the conformation of FH in fluid phase.…”

Section: Resultsmentioning

confidence: 99%

Structural modelling of human complement FHR1 and two of its synthetic derivatives provides insight into theirin-vivofunctions

Ruiz-Molina

Parsons

Decker

et al. 2022

Preprint

View full text Add to dashboard Cite

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 FHR11-2and FHR4-5. 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.

show abstract

POS-003 The three C-terminal domains of FHR1 influence complement activation and FHR1 cooperation with other complement regulators

Cited by 2 publications

References 0 publications

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

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

Structural modelling of human complement FHR1 and two of its synthetic derivatives provides insight into theirin-vivofunctions

Contact Info

Product

Resources

About