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TitleStructural basis and molecular mechanism of biased GPBAR signaling in regulating NSCLC cell growth via YAP activity.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 119, Issue 29, Page e2117054119, Year 2022
Publish dateJul 19, 2022
AuthorsLijuan Ma / Fan Yang / Xiang Wu / Chunyou Mao / Lulu Guo / Tianshu Miao / Shao-Kun Zang / Xiaoyu Jiang / Dan-Dan Shen / Tianhui Wei / Hengxing Zhou / Qin Wei / Shiyang Li / Qiang Shu / Shiqing Feng / Changtao Jiang / Bo Chu / Lutao Du / Jin-Peng Sun / Xiao Yu / Yan Zhang / Pengju Zhang /
PubMed AbstractThe G protein-coupled bile acid receptor (GPBAR) is the membrane receptor for bile acids and a driving force of the liver-bile acid-microbiota-organ axis to regulate metabolism and other ...The G protein-coupled bile acid receptor (GPBAR) is the membrane receptor for bile acids and a driving force of the liver-bile acid-microbiota-organ axis to regulate metabolism and other pathophysiological processes. Although GPBAR is an important therapeutic target for a spectrum of metabolic and neurodegenerative diseases, its activation has also been found to be linked to carcinogenesis, leading to potential side effects. Here, via functional screening, we found that two specific GPBAR agonists, R399 and INT-777, demonstrated strikingly different regulatory effects on the growth and apoptosis of non-small cell lung cancer (NSCLC) cells both in vitro and in vivo. Further mechanistic investigation showed that R399-induced GPBAR activation displayed an obvious bias for β-arrestin 1 signaling, thus promoting YAP signaling activation to stimulate cell proliferation. Conversely, INT-777 preferentially activated GPBAR-Gs signaling, thus inactivating YAP to inhibit cell proliferation and induce apoptosis. Phosphorylation of GPBAR by GRK2 at S310/S321/S323/S324 sites contributed to R399-induced GPBAR-β-arrestin 1 association. The cryoelectron microscopy (cryo-EM) structure of the R399-bound GPBAR-Gs complex enabled us to identify key interaction residues and pivotal conformational changes in GPBAR responsible for the arrestin signaling bias and cancer cell proliferation. In summary, we demonstrate that different agonists can regulate distinct functions of cell growth and apoptosis through biased GPBAR signaling and control of YAP activity in a NSCLC cell model. The delineated mechanism and structural basis may facilitate the rational design of GPBAR-targeting drugs with both metabolic and anticancer benefits.
External linksProc Natl Acad Sci U S A / PubMed:35858343 / PubMed Central
MethodsEM (single particle)
Resolution3.2 Å
Structure data

33452

7xtq

EMDB-33452, PDB-7xtq:
Cryo-EM structure of the R399-bound GPBAR-Gs complex
Method: EM (single particle) / Resolution: 3.2 Å

Chemicals

ChemComp-H8I:
[2-(2,5-Dichloro-phenoxy)-pyridin-3-yl]-(3,4-dihydro-2H-quinolin-1-yl)-methanone

Source
  • homo sapiens (human)
  • synthetic construct (others)
KeywordsMEMBRANE PROTEIN / GPCR / GPBAR / Complex / Bile acid

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