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Multimeric Interactions between Complement Factor H and Its C3d Ligand Provide New Insight on Complement Regulation

Okemefuna, AI; Li, KY; Nan, R; Ormsby, RJ; Sadlon, T; Gordon, DL; Perkins, SJ; (2009) Multimeric Interactions between Complement Factor H and Its C3d Ligand Provide New Insight on Complement Regulation. J MOL BIOL , 391 (1) 119 - 135. 10.1016/j.jmb.2009.06.013.

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Abstract

Activation of Q to C3b signals the start of the alternative complement pathway. The C-terminal short complement regulator (SCR)-20 domain of factor H (FH), the major serum regulator of C3b, possesses a binding site for C3d, a 35-kDa physiological fragment of C3b. Size distribution analyses of mixtures of SCR-16/20 or FH with C3d by analytical ultracentrifugation in 50 and 137 mM NaCl buffer revealed a range of discrete peaks, showing that multimeric complexes had formed at physiologically relevant concentrations. Surface plasmon resonance studies showed that native FH binds C3d in two stages. An equilibrium dissociation constant K-D1 of 2.6 mu M in physiological buffer was determined for the first stage. Overlay experiments indicated that C3d formed multimeric complexes with FH. X-ray scattering showed that the maximum dimension of the C3d complexes with SCR-16/20 at 29 nm was not much longer than that of the unbound SCR-16/20 dimer. Molecular modelling suggested that the ultracentrifugation and scattering data are most simply explained in terms of associating dimers of each of SCR-16/20 and C3d. We conclude that the physiological interaction between FH and C3d is not a simple 1:1 binding stoichiometry between the two proteins that is often assumed. Because the multimers involve the C-terminus of FH, which is bound to host cell surfaces, our results provide new insight on FH regulation during excessive complement activation, both in the fluid phase and at host cell surfaces decorated by C3d. (c) 2009 Elsevier Ltd. All rights reserved.

Type: Article
Title: Multimeric Interactions between Complement Factor H and Its C3d Ligand Provide New Insight on Complement Regulation
DOI: 10.1016/j.jmb.2009.06.013
Keywords: factor H, C3d, X-ray scattering, analytical ultracentrifugation, surface plasmon resonance, HEMOLYTIC-UREMIC SYNDROME, HEPARIN-BINDING DOMAIN, SHORT CONSENSUS REPEAT, X-RAY-SCATTERING, NEUTRON-SCATTERING, ANALYTICAL ULTRACENTRIFUGATION, PROTEIN BETA-1H, FACTOR-I, HYDRODYNAMIC PROPERTIES, SEDIMENTATION-VELOCITY
UCL classification: UCL > Provost and Vice Provost Offices
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
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Biochemical Engineering
URI: http://discovery.ucl.ac.uk/id/eprint/129555
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