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Published online before print April 9, 2004, 10.1110/ps.03516504
Protein Science (2004), 13:1356-1364. Published by Cold Spring Harbor Laboratory Press. Copyright © 2004 The Protein Society
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Structural stability and heat-induced conformational change of two complement inhibitors: C4b-binding protein and factor H

Lena Kask1, Bruno O. Villoutreix2, Mårten Steen1, Bala Ramesh3, Björn Dahlbäck1 and Anna M. Blom1

1 Lund University, The Wallenberg Laboratory, Department of Clinical Chemistry, University Hospital Malmö, S-205 02 Malmö, Sweden
2 French National Institute of Health and Medical Research (INSERM) U428, University Paris V, Paris, France
3 Department of Biochemistry and Molecular Biology, Royal Free and University College Medical School, London NW3 PF, UK

(RECEIVED November 17, 2003; FINAL REVISION January 23, 2004; ACCEPTED February 1, 2004)



Abstract

The complement inhibitors C4b-binding protein (C4BP) and factor H (FH) both consist of complement control protein (CCP) domains. Here we examined the secondary structure of both proteins by circular dichroism and Fourier-transform infrared technique at temperatures ranging from 30°C–90°C. We found that predominantly {beta}-sheet structure of both proteins was stable up to 70°C, and that a reversible conformational change toward {alpha}-helix was apparent at temperatures ranging from 70°C to 90°C. The ability of both proteins to inhibit complement was not impaired after incubation at 95°C, exposure to extreme pH conditions, and storage at room temperature for several months. Similar remarkable stability was previously observed for vaccinia virus control protein (VCP), which is also composed of CCP domains; it therefore seems to be a general property of CCP-containing proteins. A typical CCP domain has a hydrophobic core, which is wrapped in {beta}-sheets and stabilized by two disulphide bridges. How the CCP domains tolerate harsh conditions is unclear, but it could be due to a combination of high content of prolines, hydrophobic residues, and the presence of two disulphide bridges within each domain. These findings are of interest because CCP-containing complement inhibitors have been proposed as clinical agents to be used to control unwanted complement activation that contributes to many diseases.

Keywords: complement inhibitors; structural stability; C4b-binding protein; factor H

Abbreviations: C4BP, C4b-binding protein • FH, factor H • CCP, complement control protein • CD, circular dichroism • FTIR, Fourier transform-infrared spectroscopy • PT, prothrombin • VCP, vaccinia virus complement control protein

Reprint requests to: Anna Blom, Lund University, Department of Clinical Chemistry, University Hospital Malmö, S-205 02 Malmö, Sweden; e-mail: Anna.Blom{at}klkemi.mas.lu.se; fax: (46) 40-33-70-44.

Article published ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.03516504.


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