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Complement factor H-ligand interactions: self-association, multivalency and dissociation constants.

Perkins, SJ; Nan, R; Li, K; Khan, S; Miller, A; (2012) Complement factor H-ligand interactions: self-association, multivalency and dissociation constants. Immunobiology , 217 (2) 281 - 297. 10.1016/j.imbio.2011.10.003. Green open access

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Abstract

Factor H (FH) is the major plasma regulator of the central complement protein C3b in the alternative pathway of complement activation. The elucidation of the FH interactions with five major ligands (below) is complicated by their weak μM dissociation constants K(D) and FH multivalency. We present the first survey of all the K(D) values for the major FH-ligand interactions and critically review their physiological significance. (i) FH self-association is presently well-established. We review multiple data sets that show that 5-14% of FH is self-associated in physiological conditions. FH self-association is significant for both laboratory investigations and physiological function.(ii) The FH-C3b complex shows low M affinity, meaning that the complex is not fully formed in plasma. In addition, C3, its hydrolysed form C3u, and its cleaved forms C3b and C3d show multimerisation. Current data favour a model when two C3b molecules bind independently to one FH molecule, as opposed to a1:1 stoichiometry where FH wraps itself around C3b.(iii) Heparin is often used as an analogue of the polyanionic host cell surface. The FH-heparin complex also shows a low M affinity, again meaning that complexes are not fully formed in vivo. The oligomeric FH-heparin complexes clarify a two-site interaction model of FH with host-cell surfaces.(iv) Reinvestigation of the FH and C-reactive protein (CRP) interaction revealed that this can only occur in plasma when CRP levels are elevated during acute-phase conditions. Given that CRP binds more weakly to the His402 allotype of FH than the Tyr402 allotype, this suggested a link with age-related macular degeneration (AMD).(v) FH activity is inhibited by zinc, which causes FH to aggregate strongly. High levels of bioavailable zinc occur in sub-retinal pigment epithelial deposits which lead to AMD. Excess zinc binds weakly to a central region of FH, explaining how zinc inhibits FH regulation of C3b.

Type: Article
Title: Complement factor H-ligand interactions: self-association, multivalency and dissociation constants.
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.imbio.2011.10.003
Publisher version: http://dx.doi.org/10.1016/j.imbio.2011.10.003
Language: English
Additional information: This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: C-Reactive Protein, Complement Activation, Complement C3b, Complement Factor H, Complement Pathway, Alternative, Heparin, Humans, Ligands, Protein Binding, Zinc
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
URI: https://discovery.ucl.ac.uk/id/eprint/1335056
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