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Molecular and Cellular Biology, August 2006, p. 5838-5849, Vol. 26, No. 15
0270-7306/06/$08.00+0     doi:10.1128/MCB.00556-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

CXCR3 Requires Tyrosine Sulfation for Ligand Binding and a Second Extracellular Loop Arginine Residue for Ligand-Induced Chemotaxis

Richard A. Colvin, Gabriele S. V. Campanella, Lindsay A. Manice, and Andrew D. Luster*

Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, Massachusetts 02129

Received 29 March 2006/ Accepted 7 May 2006

CXCR3 is a G-protein-coupled seven-transmembrane domain chemokine receptor that plays an important role in effector T-cell and NK cell trafficking. Three gamma interferon-inducible chemokines activate CXCR3: CXCL9 (Mig), CXCL10 (IP-10), and CXCL11 (I-TAC). Here, we identify extracellular domains of CXCR3 that are required for ligand binding and activation. We found that CXCR3 is sulfated on its N terminus and that sulfation is required for binding and activation by all three ligands. We also found that the proximal 16 amino acid residues of the N terminus are required for CXCL10 and CXCL11 binding and activation but not CXCL9 activation. In addition, we found that residue R216 in the second extracellular loop is required for CXCR3-mediated chemotaxis and calcium mobilization but is not required for ligand binding or ligand-induced CXCR3 internalization. Finally, charged residues in the extracellular loops contribute to the receptor-ligand interaction. These findings demonstrate that chemokine activation of CXCR3 involves both high-affinity ligand-binding interactions with negatively charged residues in the extracellular domains of CXCR3 and a lower-affinity receptor-activating interaction in the second extracellular loop. This lower-affinity interaction is necessary to induce chemotaxis but not ligand-induced CXCR3 internalization, further suggesting that different domains of CXCR3 mediate distinct functions.

* Corresponding author. Mailing address: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, 149 Thirteenth Street, Room 8031, Charlestown, MA 02129. Phone: (617) 726-5710. Fax: (617) 726-5651. E-mail: aluster{at}partners.org.

Molecular and Cellular Biology, August 2006, p. 5838-5849, Vol. 26, No. 15
0270-7306/06/$08.00+0     doi:10.1128/MCB.00556-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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