A Non-Canonical Function of Gβ as a Subunit of E3 Ligase in Targeting GRK2 Ubiquitylation

Zhengyu Zha, Xiaoran Han, Matthew D. Smith, Yang Liu, Patrick M. Giguère, Dragana Kopanja, Pradip Raychaudhuri, David P. Siderovski, Kun-Liang Guan, Qun-Ying Lei, Yue Xiong
<span title="">2015</span> <i title="Elsevier BV"> <a target="_blank" rel="noopener" href="https://fatcat.wiki/container/afqwz322bfdapd7r446dhqqbbm" style="color: black;">Molecular Cell</a> </i> &nbsp;
G protein-coupled receptors (GPCRs) comprise the largest family of cell-surface receptors, regulate a wide range of physiological processes, and are the major targets of pharmaceutical drugs. Canonical signaling from GPCRs is relayed to intracellular effector proteins by trimeric G proteins, composed of α, β, and γ subunits (Gαβγ). Here, we report that G-protein β subunits (Gβ) bind to DDB1 and that Gβ2 targets GRK2 for ubiquitylation by the DDB1-CUL4A-ROC1 ubiquitin ligase. Activation of GPCR
more &raquo; ... esults in PKA-mediated phosphorylation of DDB1 at Ser645 and its dissociation from Gβ2, leading to increase of GRK2 protein. Deletion of Cul4a results in cardiac hypertrophy in male mice that can be partially rescued by the deletion of one Grk2 allele. These results reveal a non-canonical function of the Gβ protein as a ubiquitin ligase component and a mechanism of feedback regulation of GPCR signaling. Previously, we and other groups reported that human cells express as many as ninety DDB1binding WD40 proteins (DWD, also known as DCAF for DDB1-and CUL4-associated factors and CDW for CUL4 and DDB1-associated WD40 repeats) {Angers, 2006 #90; He, 2006 #24; Higa, 2006 #25; Jin, 2006 #117}. Among these estimated 90 human DWD proteins are the five members of the G-protein β subunits (Gβs) (Gβ1 -5). Structurally, each Zha et al.
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