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J. Biol. Chem., Vol. 275, Issue 48, 37692-37701, December 1, 2000
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From the Membrane cofactor protein (MCP; CD46), a widely
distributed regulator of complement activation, is a cofactor for the
factor I-mediated degradation of C3b and C4b deposited on host cells. MCP possesses four extracellular, contiguous complement control protein
modules (CCPs) important for this inhibitory activity. The goal of the
present study was to delineate functional sites within these modules.
We employed multiple approaches including mutagenesis, epitope mapping,
and comparisons to primate MCP to make the following observations.
First, functional sites were located to each of the four CCPs. Second,
some residues were important for both C3b and C4b interactions while
others were specific for one or the other. Third, while a reduction in
ligand binding was invariably accompanied by a parallel reduction in
cofactor activity (CA), other mutants lost or had reduced CA but
retained ligand binding. Fourth, two C4b-regulatory domains overlapped
measles virus interactive regions, indicating that the hemagglutinin
docks to a site important for complement inhibition. Fifth, several MCP
regulatory areas corresponded to functionally critical, homologous positions in other CCP-bearing C3b/C4b-binding proteins. Based on these
data and the recently derived crystal structure of repeats one and two,
computer modeling was employed to predict MCP structure and examine
active sites.
Dissecting Sites Important for Complement Regulatory Activity in
Membrane Cofactor Protein (MCP; CD46)*
,,,,
Division of Rheumatology, Department
of Medicine, Washington University School of Medicine, St. Louis,
Missouri 63110, the ¶ Division of Virology, Department of
Neuropharmacology, Scripps Research Institute, La Jolla, California
92037, and the § Edinburgh Centre for Protein Technology,
Joseph Black Chemistry Building, West Mains Road, Edinburgh EH9
3JJ, Scotland
*
This work was supported by National Institutes of Health
Grant R01 AI37618.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Div. of
Rheumatology, Washington University School of Medicine, 660 S. Euclid Ave., Box 8045, St. Louis, MO 63110. Tel.: 314-362-8391; Fax: 314-362-1366; E-mail: jatkinso@im.wustl.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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