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Allosteric mechanisms underlie GPCR signaling to SH3-domain proteins through arrestin, Nat Chem Biol, 17 August 2018
2018-08-22 | 【     】【打印】【关闭

Nat Chem Biol, 17 August 2018

Allosteric mechanisms underlie GPCR signaling to SH3-domain proteins through arrestin

Fan Yang, Peng Xiao, Chang-xiu Qu, Qi Liu, Liu-yang Wang, Zhi-xin Liu, Qing-tao He, Chuan Liu, Jian-ye Xu, Rui-rui Li, Meng-jing Li, Qing Li, Xu-zhen Guo, Zhao-ya Yang, Dong-fang He, Fan Yi, Ke Ruan, Yue-mao Shen, Xiao Yu, Jin-peng Sun & Jiangyun Wang

Abstract

Signals from 800 G-protein-coupled receptors (GPCRs) to many SH3 domain-containing proteins (SH3-CPs) regulate important physiological functions. These GPCRs may share a common pathway by signaling to SH3-CPs via agonist-dependent arrestin recruitment rather than through direct interactions. In the present study, 19F-NMR and cellular studies revealed that downstream of GPCR activation engagement of the receptor-phospho-tail with arrestin allosterically regulates the specific conformational states and functional outcomes of remote β-arrestin 1 proline regions (PRs). The observed NMR chemical shifts of arrestin PRs were consistent with the intrinsic efficacy and specificity of SH3 domain recruitment, which was controlled by defined propagation pathways. Moreover, in vitro reconstitution experiments and biophysical results showed that the receptor–arrestin complex promoted SRC kinase activity through an allosteric mechanism. Thus, allosteric regulation of the conformational states of β-arrestin 1 PRs by GPCRs and the allosteric activation of downstream effectors by arrestin are two important mechanisms underlying GPCR-to-SH3-CP signaling.

文章链接:https://www.nature.com/articles/s41589-018-0115-3

相关报道:http://www.ibp.cas.cn/kyjz/zxdt/201808/t20180822_5058259.html

 

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