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Protein Science (2004), 13:1238-1250. Published by Cold Spring Harbor Laboratory Press. Copyright © 2004 The Protein Society
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Backbone dynamics of complement control protein (CCP) modules reveals mobility in binding surfaces

Joanne M. O'Leary1,2, Krystyna Bromek1, Gordon M. Black, Stanislava Uhrinova, Christian Schmitz3, Xuefeng Wang4, Malgorzata Krych4, John P. Atkinson4, Dusan Uhrin and Paul N. Barlow

Schools of Chemistry and Biology, University of Edinburgh, Edinburgh EH9 3JJ, Scotland

(RECEIVED December 18, 2003; FINAL REVISION January 27, 2004; ACCEPTED February 1, 2004)



Abstract

The regulators of complement activation (RCA) are critical to health and disease because their role is to ensure that a complement-mediated immune response to infection is proportionate and targeted. Each protein contains an uninterrupted array of from four to 30 examples of the very widely occurring complement control protein (CCP, or sushi) module. The CCP modules mediate specific protein–protein and protein–carbohydrate interactions that are key to the biological function of the RCA and, paradoxically, provide binding sites for numerous pathogens. Although structural and mutagenesis studies of CCP modules have addressed some aspects of molecular recognition, there have been no studies of the role of molecular dynamics in the interaction of CCP modules with their binding partners. NMR has now been used in the first full characterization of the backbone dynamics of CCP modules. The dynamics of two individual modules—the 16th of the 30 modules of complement receptor type 1 (CD35), and the N-terminal module of membrane cofactor protein (CD46)—as well as their solution structures, are compared. Although both examples share broadly similar three-dimensional structures, many structurally equivalent residues exhibit different amplitudes and timescales of local backbone motion. In each case, however, regions of the module-surface implicated by mutagenesis as sites of interactions with other proteins include several mobile residues. This observation suggests further experiments to explore binding mechanisms and identify new binding sites.

Keywords: CCP module; SCR; complement; backbone dynamics; NMR

Abbreviations: CCP, complement control protein • CR1, complement receptor type 1 • MCP, membrane cofactor protein • NOE(sy), nuclear Overhauser effect (spectroscopy) • NMR, nuclear magnetic resonance spectroscopy • RCA, regulators of complement activation • rms, root mean square • TOCSY, total correlation spectroscopy

Reprint requests to: Paul Barlow, Schools of Chemistry and Biology, Joseph Black Chemistry Building, University of Edinburgh, West Mains Road, Edinburgh, EH9 3JJ, Scotland; e-mail: Paul.Barlow{at}ed.ac.uk; fax: 44-1-31-650-7055.

1 These authors contributed equally to this work.

2 Present addresses: Department of Biochemistry, University of Oxford, OX1 3Q4, UK;

3 Biophysical Chemistry Group, Institute of Physical Chemistry, University of Heidelberg, D-69120, Germany;

4 Washington University School of Medicine, St. Louis, MO 63110, USA.

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.03582704.


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