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Arginine 313 of the putative 8th helix mediates Gαq/14 coupling of human CC chemokine receptors CCR2a and CCR2b.
Cellular Signalling ( IF 4.4 ) Pub Date : 2018-10-12 , DOI: 10.1016/j.cellsig.2018.10.007
Daniel Markx 1 , Julia Schuhholz 1 , Michael Abadier 1 , Sandra Beier 1 , Mariana Lang 1 , Barbara Moepps 1
Affiliation  

In man, two CC chemokine receptor isoforms, CCR2a and CCR2b, are present that belong to the rhodopsin-like G protein-coupled receptor family, and couple to Gi and Gq family members. The CCR2 receptors are known to regulate canonical functions of chemokines such as directed migration of leukocytes, and to potentially control non-canonical functions such as differentiation, proliferation, and gene transcription of immune and non-immune cells. We recently reported on the activation of phospholipase C isoenzymes and RhoA GTPases by coupling of the two CCR2 receptors to members of the Gq family, in particular Gαq and Gα14. So far little is known about the structural requirements for the CCR2/Gq/14 interaction. Interestingly, the CCR2 receptor isoforms are identical up to arginine 313 (R313) that is part of the putative 8th helix in CCR2 receptors, and the 8th helix has been implicated in the interaction of rhodopsin-like G protein-coupled receptors with Gαq. In the present work we describe that the 8th helix of both CCR2a and CCR2b is critically involved in selectively activating Gαq/14-regulated signaling. Refined analysis using various CCR2a and CCR2b mutants and analyzing their cellular signaling, e.g. ligand-dependent (i) activation of phospholipase C isoenzymes, (ii) stimulation of serum response factor-mediated gene transcription, (iii) activation of mitogen-activated protein kinases, (iv) internalization, and (v) changes in intracellular calcium concentrations, identified arginine 313 within the amino terminal portion of helix 8 to play a role for the agonist-mediated conformational changes and the formation of a Gαq/14 binding surface. We show that R313 determines Gαq/14 protein-dependent but not Gi protein-dependent cellular signaling, and plays no role in Gq/Gi-independent receptor internalization, indicating a role of R313 in biased signaling of CCR2 receptors.

中文翻译:

推测的第8个螺旋的精氨酸313介导人CC趋化因子受体CCR2a和CCR2b的Gαq/ 14偶联。

在人类中,存在两种CC趋化因子受体亚型CCR2a和CCR2b,它们属于视紫红质样G蛋白偶联受体家族,并与Gi和Gq家族成员偶联。已知CCR2受体可调节趋化因子的规范功能,例如白细胞的定向迁移,并潜在地控制非规范功能,例如免疫细胞和非免疫细胞的分化,增殖和基因转录。我们最近报道了通过两个CCR2受体与Gq家族成员,特别是Gαq和Gα14偶联,激活磷脂酶C同工酶和RhoA GTPases的过程。到目前为止,对CCR2 / Gq / 14相互作用的结构要求知之甚少。有趣的是,CCR2受体亚型与精氨酸313(R313)相同,而精氨酸313是CCR2受体中第8个螺旋的一部分,而第8螺旋与视紫红质样G蛋白偶联受体与Gαq的相互作用有关。在当前的工作中,我们描述了CCR2a和CCR2b的第8个螺旋都关键地参与了选择性激活Gαq/ 14调控信号的过程。使用各种CCR2a和CCR2b突变体进行精细分析并分析其细胞信号传导,例如依赖配体的(i)激活磷脂酶C同工酶,(ii)刺激血清反应因子介导的基因转录,(iii)激活有丝分裂原激活的蛋白激酶,(iv)内在化和(v)细胞内钙浓度的变化,确定了螺旋8氨基末端部分的精氨酸313在激动剂介导的构象变化和Gαq/ 14结合表面的形成中起作用。
更新日期:2018-10-12
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