Structural mechanism underlying G protein family-specific regulation of G protein-gated inwardly rectifying potassium channel
Structural mechanism underlying G protein family-specific regulation of G protein-gated inwardly rectifying potassium channel
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DOI：
10.1038/s41467-019-10038-x
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发表时间：
2019-05-01
影响因子：
16.6
通讯作者：
Shimada, Ichio
中科院分区：
文献类型：
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作者：
Kano, Hanaho;Toyama, Yuki;Shimada, Ichio
G蛋白门控内向整流钾通道（GIRK）在神经传递中起着重要的调节作用。GIRK通过G蛋白β γ亚基（G β γ）的直接结合而打开，所述G蛋白β γ亚基在G蛋白偶联受体（GPCR）活化时从异源三聚体G蛋白（G α β γ）释放。GIRK通过特异性和有效地响应Gi/o偶联的GPCR而有助于精确的细胞应答。然而，这种家族特异性和有效激活的详细机制在很大程度上是未知的。在这里，我们调查的Gi/o家族特异性激活GIRK的结构机制，结合基于细胞的BRET实验和NMR分析在一个重建的膜环境。我们发现，由G α i/o的α A螺旋形成的相互作用介导了G α i/omicron β γ-GIRK复合物的形成，该复合物负责GIRK的家族特异性激活。我们还提出了一个模型结构的G α i/omicron β γ-GIRK复合物，这提供了潜在的特异性和有效的调节GIRK的分子基础。
G protein-gated inwardly rectifying potassium channel (GIRK) plays a key role in regulating neurotransmission. GIRK is opened by the direct binding of the G protein beta gamma subunit (G beta gamma), which is released from the heterotrimeric G protein (G alpha beta gamma) upon the activation of G protein-coupled receptors (GPCRs). GIRK contributes to precise cellular responses by specifically and efficiently responding to the Gi/o-coupled GPCRs. However, the detailed mechanisms underlying this family-specific and efficient activation are largely unknown. Here, we investigate the structural mechanism underlying the Gi/o family-specific activation of GIRK, by combining cell-based BRET experiments and NMR analyses in a reconstituted membrane environment. We show that the interaction formed by the alpha A helix of G alpha i/o mediates the formation of the G alpha i/omicron beta gamma-GIRK complex, which is responsible for the family-specific activation of GIRK. We also present a model structure of the G alpha i/omicron beta gamma-GIRK complex, which provides the molecular basis underlying the specific and efficient regulation of GIRK.