期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 26, 期 15, 页码 5838-5849出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00556-06
关键词
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资金
- NCI NIH HHS [R01 CA069212, R01 CA69212] Funding Source: Medline
- NIAID NIH HHS [K08 AI50147] Funding Source: Medline
- NIDDK NIH HHS [P01 DK50305, R01 DK07449, P01 DK050305, T32 DK007449] Funding Source: Medline
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 8216 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.
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