Bioluminescence resonance energy transfer reveals ligand-induced conformational changes in CXCR4 homo- and heterodimers
Bioluminescence resonance energy transfer reveals ligand-induced conformational changes in CXCR4 homo- and heterodimers
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DOI：
10.1074/jbc.m411151200
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发表时间：
2005-03-18
影响因子：
4.8
通讯作者：
Heveker, N
中科院分区：
文献类型：
--
作者：
Percherancier, Y;Berchiche, YA;Heveker, N
同源和异源二聚体已成为G蛋白偶联受体的突出特征，可能影响其活性的调节。利用灵敏的生物发光共振能量转移系统，我们研究了趋化因子受体CXCR4和CCR2二聚体的形成。我们发现，这两种受体存在的组成同源和异源二聚体和配体诱导内的预形成的二聚体的构象变化，而不促进受体二聚体的形成或拆卸。具有不同内在功效的配体产生不同的生物发光共振能量转移调制，表明不同受体构象的稳定。我们还发现，CXCR4的跨膜结构域衍生的肽通过阻断配体诱导的二聚体的构象转变来抑制该受体的活化。两者合计，我们的数据支持一个模型，其中趋化因子受体同源和异源二聚体的形式自发和响应配体结合的单位，经历构象变化，涉及两个原聚体，即使只有一个两个配体结合位点被占用。
Homo- and heterodimerization have emerged as prominent features of G-protein- coupled receptors with possible impact on the regulation of their activity. Using a sensitive bioluminescence resonance energy transfer system, we investigated the formation of CXCR4 and CCR2 chemokine receptor dimers. We found that both receptors exist as constitutive homo- and heterodimers and that ligands induce conformational changes within the pre-formed dimers without promoting receptor dimer formation or disassembly. Ligands with different intrinsic efficacies yielded distinct bioluminescence resonance energy transfer modulations, indicating the stabilization of distinct receptor conformations. We also found that peptides derived from the transmembrane domains of CXCR4 inhibited activation of this receptor by blocking the ligand-induced conformational transitions of the dimer. Taken together, our data support a model in which chemokine receptor homo- and heterodimers form spontaneously and respond to ligand binding as units that undergo conformational changes involving both protomers even when only one of the two ligand binding sites is occupied.