Yeast GPCR signaling reflects the fraction of occupied receptors, not the number.
Yeast GPCR signaling reflects the fraction of occupied receptors, not the number.
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DOI：
10.15252/msb.20166910
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发表时间：
2016-12-29
影响因子：
9.9
通讯作者：
Colman-Lerner A
中科院分区：
文献类型：
--
作者：
Bush A;Vasen G;Constantinou A;Dunayevich P;Patop IL;Blaustein M;Colman-Lerner A
根据受体理论，配体的作用取决于激动剂-受体复合物的量。因此，受体丰度的变化应该具有定量效应。然而，酿酒酵母对信息素的反应对G蛋白偶联受体（GPCR）Ste 2丰度的增加或减少是稳健的（未改变），而不是对占用受体的分数作出反应。我们通过实验发现，这种鲁棒性起源于G蛋白激活期间。我们为这一步开发了一个完整的数学模型，这表明计算占有率的能力取决于G蛋白信号传导抑制调节因子（RGS）Sst 2和受体之间的物理相互作用。因此，用不能与受体相互作用的异源hsRGS 4替代Sst 2，消除了稳健性。相反，强制hsRGS 4：Ste 2相互作用恢复了稳健性。结合我们工作的其他结果，我们得出结论，这种GPCR途径计算分数占用，因为配体结合的GPCR-RGS复合物刺激信号传导，而未占用的复合物积极抑制它。在真核生物中，许多RGS结合到特定的GPCR，这表明这些具有相反活性的复合物也通过比率测量检测分数占用。这种复合物作为推拉装置工作，我们最近描述了这一点。
According to receptor theory, the effect of a ligand depends on the amount of agonist–receptor complex. Therefore, changes in receptor abundance should have quantitative effects. However, the response to pheromone in Saccharomyces cerevisiae is robust (unaltered) to increases or reductions in the abundance of the G‐protein‐coupled receptor (GPCR), Ste2, responding instead to the fraction of occupied receptor. We found experimentally that this robustness originates during G‐protein activation. We developed a complete mathematical model of this step, which suggested the ability to compute fractional occupancy depends on the physical interaction between the inhibitory regulator of G‐protein signaling (RGS), Sst2, and the receptor. Accordingly, replacing Sst2 by the heterologous hsRGS4, incapable of interacting with the receptor, abolished robustness. Conversely, forcing hsRGS4:Ste2 interaction restored robustness. Taken together with other results of our work, we conclude that this GPCR pathway computes fractional occupancy because ligand‐bound GPCR–RGS complexes stimulate signaling while unoccupied complexes actively inhibit it. In eukaryotes, many RGSs bind to specific GPCRs, suggesting these complexes with opposing activities also detect fraction occupancy by a ratiometric measurement. Such complexes operate as push‐pull devices, which we have recently described.