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J. Biol. Chem., Vol. 276, Issue 36, 33906-33914, September 7, 2001
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From the Fractalkine/CX3CL1 is a membrane-tethered
chemokine that functions as a chemoattractant and adhesion protein by
interacting with the receptor CX3CR1. To understand the molecular basis
for the interaction, an extensive mutagenesis study of fractalkine's chemokine domain was undertaken. The results reveal a cluster of basic
residues (Lys-8, Lys-15, Lys-37, Arg-45, and Arg-48) and one
aromatic (Phe-50) that are critical for binding and/or signaling. The
mutant R48A could bind but not induce chemotaxis, demonstrating that
Arg-48 is a signaling trigger. This result also shows that signaling
residues are not confined to chemokine N termini, as generally thought.
F50A showed no detectable binding, underscoring its importance to the
stability of the complex. K15A displayed unique signaling
characteristics, eliciting a wild-type calcium flux but minimal
chemotaxis, suggesting that this mutant can activate some, but not all,
pathways required for migration. Fractalkine also binds the human
cytomegalovirus receptor US28, and analysis of the mutants indicates
that US28 recognizes many of the same epitopes of fractalkine as
CX3CR1. Comparison of the binding surfaces of fractalkine and the
CC chemokine MCP-1 reveals structural details that may account for
their dual recognition by US28 and their selective recognition by
host receptors.
Molecular Determinants of Receptor Binding and Signaling by the
CX3C Chemokine Fractalkine*,
§,
,, and§§
Department of Molecular and Cell Biology and
the Howard Hughes Medical Institute, University of California,
Berkeley, California 94720, ¶ Neurocrine Biosciences Inc., San
Diego, California 92121, and the ** Laboratory for Molecular
Pharmacology, Panum Institute 18.6, Blegdamsvej 3B,
DK-2200 Copenhagen, Denmark
*
This work was supported by the National Institutes of Health
and American Heart Association grants (to T. M. H.)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.
The on-line version of this article (available at
http://www.jbc.org) contains a complete summary of the binding,
chemotaxis, and calcium flux data.
§
Current address: Dept. of Biochemistry, Vanderbilt University,
Nashville, TN 37232-0146.
To whom correspondence may be addressed. Current address: Bayer
Yakuhin Ltd., 6-5-1-3 Kunimidai, Kizu-cho, Soraku-gun, Kyoto 610-0216, Japan. Tel.: 81-774-75-2473; Fax: 81-774-75-2506; E-mail: kevin.bacon.kb@bayer.co.jp.
§§
To whom correspondence may be addressed. Tel.:
510-643-9313; Fax: 510-643-9290; E-mail:
handel@paradise1.berkeley.edu.
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