Homo- and hetero-dimeric subunit interactions set affinity and efficacy in metabotropic glutamate receptors.
Homo- and hetero-dimeric subunit interactions set affinity and efficacy in metabotropic glutamate receptors.
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同源和异源二聚体亚基相互作用在代谢型谷氨酸受体中设定亲和力和功效。
DOI：
10.1038/s41467-023-44013-4
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发表时间：
2023-12-13
影响因子：
16.6
通讯作者：
Isacoff, Ehud Y.
中科院分区：
文献类型：
--
作者：
Habrian, Chris;Latorraca, Naomi;Fu, Zhu;Isacoff, Ehud Y.
代谢型谷氨酸受体（mGluRs）是在神经胶质和神经元中起作用的二聚C类G蛋白偶联受体。谷氨酸亲和力和功效在八种mGluR之间变化很大。这种多样性的分子基础尚不清楚。我们使用单分子荧光能量转移来监测mGluR配体结合域（LBD）中激活的结构重排。在饱和谷氨酸时，II组同源二聚体完全占据活化的LBD构象（完全功效），但III组mGluRs的同源二聚体不占据。引人注目的是，第III组同源二聚体的降低的功效并不是由谷氨酸结合口袋中的差异引起的，而是由细胞外二聚化界面内的相互作用引起的，所述相互作用阻碍活性状态占据。相比之下，功能增强的mGluR II/III异二聚体缺乏这些界面“制动器"激活和异二聚体的不对称性的二硫环连接LBD的灵活性大大有利于激活构象的占用。我们的结果表明，二聚化界面相互作用通过差异稳定活化构象产生了大量的功能多样性。这种多样性可以优化mGluR的响应突触与突触外谷氨酸的不同时空配置文件。强制性二聚体mGluRs之间功能多样性的分子基础尚不清楚。作者表明，通常归因于激动剂结合口袋差异的功能差异来自二聚化界面相互作用中的同聚和异聚II和III组GI偶联mGluR之间的差异。
Metabotropic glutamate receptors (mGluRs) are dimeric class C G-protein–coupled receptors that operate in glia and neurons. Glutamate affinity and efficacy vary greatly between the eight mGluRs. The molecular basis of this diversity is not understood. We used single-molecule fluorescence energy transfer to monitor the structural rearrangements of activation in the mGluR ligand binding domain (LBD). In saturating glutamate, group II homodimers fully occupy the activated LBD conformation (full efficacy) but homodimers of group III mGluRs do not. Strikingly, the reduced efficacy of Group III homodimers does not arise from differences in the glutamate binding pocket but, instead, from interactions within the extracellular dimerization interface that impede active state occupancy. By contrast, the functionally boosted mGluR II/III heterodimers lack these interface ‘brakes’ to activation and heterodimer asymmetry in the flexibility of a disulfide loop connecting LBDs greatly favors occupancy of the activated conformation. Our results suggest that dimerization interface interactions generate substantial functional diversity by differentially stabilizing the activated conformation. This diversity may optimize mGluR responsiveness for the distinct spatio-temporal profiles of synaptic versus extrasynaptic glutamate. The molecular basis of functional diversity between obligatorily dimeric mGluRs is not understood. The authors show that functional differences typically attributed to differences in the agonist binding pocket emerge from differences between homomeric and heteromeric Group II and III Gi-coupled mGluRs in dimerization interface interactions.
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影响因子：
16.8
作者：
Kniazeff, J;Bessis, AS;Pin, JP
通讯作者：
Pin, JP
DOI：
10.1146/annurev.pharmtox.011008.145533
发表时间：
2010
影响因子：
12.5
作者：
Niswender CM;Conn PJ
通讯作者：
Conn PJ
蛋白质动力学在GPCR功能中的作用：β2AR和视紫红质的见解。
影响因子：
7.5
作者：
Manglik, Aashish;Kobilka, Brian
通讯作者：
Kobilka, Brian
影响因子：
13.8
作者：
Ellaithy A;Gonzalez-Maeso J;Logothetis DA;Levitz J
通讯作者：
Levitz J
影响因子：
64.8
作者：
Du, Juan;Wang, Dejian;Zhao, Qiang
通讯作者：
Zhao, Qiang