A model for how Gβγ couples Gα to GPCR.
A model for how Gβγ couples Gα to GPCR.
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DOI：
10.1085/jgp.202112982
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发表时间：
2022-05-02
期刊：
影响因子：
--
通讯作者：
McIntire WE
中科院分区：
文献类型：
--
作者：
McIntire WE
异源三聚体G蛋白含有α亚基和βγ二聚体，它们将G蛋白偶联受体(GPCRs)的信号传递到细胞内环境。麦金泰尔提出了一个模型，在该模型中，G-βγ和G-α之间的初始相互作用使受体为随后与G-DNA的相互作用做好准备。G蛋白偶联受体(∼)占人类基因组的5%，是药物发现的主要靶点；然而，关于它们如何与异源三聚体G蛋白亚基偶联的分子细节还不完全清楚。在这里，我提出了一个假想的GPCR与Gβγ相遇的初始对接模型，该模型定义了GPCR的胞液表面与Gγ亚单位C末端的戊烯基部分和三肽基序天冬氨酸-脯氨酸-苯丙氨酸之间的瞬时相互作用。对A类GPCRs的分析表明，TM1和H8相互作用形成了保守的NPF结合位点。使用不同的异戊烯基化蛋白质和多肽进行的功能研究进一步表明，GPCR的细胞内疏水核心是异戊烯基结合部位。当与GPCRs的TM1和H8结合时，Gγ的C-末端区域转换为α螺旋的倾向使其能够延伸到GPCRs的疏水核心，促进GPCRs的活性状态。Gγ亚型中NPF基序的保守性以及TM1和H8中的相互作用残基表明这是GPCRG蛋白信号转导的一般机制。对视紫红质二聚体的分析还表明，Gγ-视紫红质相互作用可能促进GPCR二聚体的反式激活。
The heterotrimeric G protein contains an α subunit and βγ dimer, which relay signals from G-protein-coupled receptors (GPCRs) to the intracellular milieu. McIntire proposes a model in which initial interactions between Gβγ and GPCR prime the receptor for subsequent interactions with Gα. Representing ∼5% of the human genome, G-protein-coupled receptors (GPCRs) are a primary target for drug discovery; however, the molecular details of how they couple to heterotrimeric G protein subunits are incompletely understood. Here, I propose a hypothetical initial docking model for the encounter between GPCR and Gβγ that is defined by transient interactions between the cytosolic surface of the GPCR and the prenyl moiety and the tripeptide motif, asparagine–proline–phenylalanine (NPF), in the C-terminus of the Gγ subunit. Analysis of class A GPCRs reveals a conserved NPF binding site formed by the interaction of the TM1 and H8. Functional studies using differentially prenylated proteins and peptides further suggest that the intracellular hydrophobic core of the GPCR is a prenyl binding site. Upon binding TM1 and H8 of GPCRs, the propensity of the C-terminal region of Gγ to convert into an α helix allows it to extend into the hydrophobic core of the GPCR, facilitating the GPCR active state. Conservation of the NPF motif in Gγ isoforms and interacting residues in TM1 and H8 suggest that this is a general mechanism of GPCR–G protein signaling. Analysis of the rhodopsin dimer also suggests that Gγ–rhodopsin interactions may facilitate GPCR dimer transactivation.
影响因子：
2.9
作者：
Katadae, Maiko;Hagiwara, Ken'ichi;Wada, Akimori;Ito, Masayoshi;Umeda, Masato;Casey, Patrick J.;Fukada, Yoshitaka
通讯作者：
Fukada, Yoshitaka