Molecular characterization of the chemokine receptor CXCR3: evidence for the involvement of distinct extracellular domains in a multi-step model of ligand binding and receptor activation
Molecular characterization of the chemokine receptor CXCR3: evidence for the involvement of distinct extracellular domains in a multi-step model of ligand binding and receptor activation
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DOI：
10.1002/eji.200324235
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发表时间：
2003-10-01
影响因子：
5.4
通讯作者：
Pease, JE
中科院分区：
文献类型：
--
作者：
Xanthou, G;Williams, TJ;Pease, JE
CXCR 3是主要在T淋巴细胞上表达的趋化因子受体，并结合趋化因子CXCL 9（Mig）、CXCL 10（IP-10）和CXCL 11（I-TAC）。在这里，我们研究了CXCR 3的胞外结构域的配体选择性和受体活化的嵌合CXCR 3/CXCR 1结构的配体结合和趋化反应进行评估的作用。我们的数据表明，CXCR 3的第二个细胞外环是必不可少的受体激活响应所有CXCR 3配体。相反，CXCR 3的N末端和第一个细胞外环在CXCL 10和CXCL 11介导的活化中起一定作用，但在CXCL 9诱导的信号传导中不起作用。CXCR 3的第三胞外环仅对CXCL 9和CXCL 10诱导的趋化性重要。结合研究表明，CXCR 3配体结合到由CXCR 3的多个结构域组成的不同位点，并且高亲和力结合和受体活化是不同的功能。总的来说，我们的数据支持CXCR 3与其激动剂相互作用的多位点模型，其中CXCR 3的几个胞外结构域有助于配体结合和诱导受体活化。靶向CXCR 3的第二细胞外环的拮抗剂的开发应阻止受体活化并有助于治疗几种人类炎性疾病。
CXCR3 is a chemokine receptor predominantly expressed on T lymphocytes, and binds the chemokines CXCL9 (Mig), CXCL10 (IP-10) and CXCL11 (I-TAC). Here, we have investigated the role of the extracellular domains of CXCR3 in ligand selectivity and receptor activation by assessing the ligand binding and chemotactic responses of chimeric CXCR3/CXCR1 constructs. Our data reveal that the second extracellular loop of CXCR3 is essential for receptor activation in response to all CXCR3 ligands. In contrast, the N terminus and first extracellular loop of CXCR3 play some role in CXCL10- and CXCL11-mediated activation but are dispensable for CXCL9-induced signaling. The third extracellular loop of CXCR3 is important only for CXCL9- and CXCL10-induced chemotaxis. Binding studies suggest that the CXCR3 ligands bind to distinct sites composed of multiple domains of CXCR3 and that high-affinity binding and receptor activation are disparate functions. Collectively, our data support a multi-site model for CXCR3 interactions with its agonists, in which several extracellular domains of CXCR3 contribute to ligand binding and the induction of receptor activation. The development of antagonists targeting the second extracellular loop of CXCR3 should impede receptor activation and aid the treatment of several human inflammatory disorders.