The Journal of Experimental Medicine
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Published online 7 May 2001.
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© The Rockefeller University Press, 0022-1007/2001/5/1059/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 9, May 7, 2001 1059-1066

Original Article

Sulfated Tyrosines Contribute to the Formation of the C5a Docking Site of the Human C5a Anaphylatoxin Receptor

Michael Farzana, Christine E. Schnitzlerb, Natalya Vasilievab, Doris Leungb, Jens Kuhna, Craig Gerardb, Norma P. Gerardb, and Hyeryun Choeb

a Department of Cancer Immunology and AIDS, Dana Farber Cancer Institute, Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115
b Perlmutter Laboratory, Children's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115
Perlmutter Laboratory, Children's Hospital, Boston, MA 02115.617-632-3113617-355-7586

hchoe{at}mbcrr.harvard.edu

The complement anaphylatoxin C5a and its seven-transmembrane segment (7TMS) receptor play an important role in host defense and in a number of inflammation-associated pathologies. The NH2-terminal domain of the C5a receptor (C5aR/CD88) contributes substantially to its ability to bind C5a. Here we show that the tyrosines at positions 11 and 14 of the C5aR are posttranslationally modified by the addition of sulfate groups. The sulfate moieties of each of these tyrosines are critical to the ability of the C5aR to bind C5a and to mobilize calcium. A C5aR variant lacking these sulfate moieties efficiently mobilized calcium in response to a small peptide agonist, but not to C5a, consistent with a two-site model of ligand association in which the tyrosine-sulfated region of the C5aR mediates the initial docking interaction. A peptide based on the NH2 terminus of the C5aR and sulfated at these two tyrosines, but not its unsulfated analogue or a doubly sulfated control peptide, partially inhibited C5a association with its receptor. These observations clarify structural and mutagenic studies of the C5a/C5aR association and suggest that related 7TMS receptors are also modified by functionally important sulfate groups on their NH2-terminal tyrosines.

Key Words: C5a • C5aR • tyrosine sulfation • chemotactic receptors • CD88

Abbreviations used in this paper: CCR5, CC chemokine receptor 5; Cha, cyclohexylalanine; NMR, nuclear magnetic resonance; 7TMS, seven-transmembrane segment.

© 2001 The Rockefeller University Press


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