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J. Biol. Chem., Vol. 279, Issue 1, 142-151, January 2, 2004

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C5a Mutants Are Potent Antagonists of the C5a Receptor (CD88) and of C5L2

POSITION 69 IS THE LOCUS THAT DETERMINES AGONISM OR ANTAGONISM^*

Magnus Otto, Heiko Hawlisch¶, Peter N. Monk||, Melanie Müller, Andreas Klos, Christopher L. Karp¶, and Jörg Köhl¶**

From the Institute of Medical Microbiology, Medical School Hannover, 30625 Hannover, Germany, the ^¶Division of Molecular Immunology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio 45229, and the ^||Department of Neurology, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, United Kingdom

The anaphylatoxin C5a exerts a plethora of biologic activities critical in the pathogenesis of systemic inflammatory diseases. Recently, we reported on a C5a mutant, jun/fos-A8, as a potent antagonist for the human and mouse C5a receptor (CD88). Addressing the molecular mechanism accounting for CD88 receptor antagonism by site-directed mutagenesis, we found that a positively charged amino acid at position 69 is crucial. Replacements by either hydrophobic or negatively charged amino acids switched the CD88 antagonist jun/fos-A8 to a CD88 agonist. In addition to CD88, the seven-transmembrane receptor C5L2 has recently been found to provide high affinity binding sites for C5a and its desarginated form, C5adesArg⁷⁴. A jun/fos-A8 mutant in which the jun/ fos moieties and amino acids at positions 71–73 were deleted, A8^71–73, blocked C5a and C5adesArg⁷⁴ binding to CD88 and C5L2. In contrast, the cyclic C5a C-terminal analog peptide AcF-[OP-D-ChaWR] inhibited binding of the two anaphylatoxins to CD88 but not to C5L2, suggesting that the C5a core segment is important for high affinity binding to C5L2. Both receptors are coexpressed on human monocytes and the human mast cell line HMC-1; however, C5L2 expression on monocytes is weaker as compared with HMC-1 cells and highly variable. In contrast, no C5L2 expression was found on human neutrophils. A8^71–73 is the first antagonist that blocks C5a and C5adesArg⁷⁴ binding to both C5a receptors, CD88 and C5L2, making it a valuable tool for studying C5L2 functions and for blocking the biological activities of C5a and C5adesArg⁷⁴ in mice and humans.

Received for publication, September 10, 2003 , and in revised form, October 15, 2003.

^* This work was supported by Cincinnati Children's Hospital Research Foundation funding and by Deutsche Forschungsgemeinschaft Grant KO 1245/1-1 (to J. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^** To whom correspondence should be addressed: Div. of Molecular Immunology, Cincinnati Children's Hospital Research Foundation, MLC 7021, Cincinnati, OH 45229. Tel.: 513-636-1219; Fax: 513-636-5355; E-mail: Joerg.Koehl{at}chmcc.org.

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