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Illuminating G-protein-coupling selectivity of GPCRs

Summary - Heterotrimetic G proteins consist of four subfamilies (Gs, Gi/o, Gq/11, and G12/13) that mediate signaling via G-protein-coupled receptors (GPCRs), principally by receptors binding Gα C termini. G-protein-coupling profiles govern GPCR-induced cellular responses, yet receptor sequence selec...

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Main Authors: Inoue, Asuka (Author) , Raimondi, Francesco (Author) , Kadji, Francois Marie Ngako (Author) , Singh, Gurdeep (Author) , Kishi, Takayuki (Author) , Uwamizu, Akiharu (Author) , Ono, Yuki (Author) , Shinjo, Yuji (Author) , Ishida, Satoru (Author) , Arang, Nadia (Author) , Kawakami, Kouki (Author) , Gutkind, J. Silvio (Author) , Aoki, Junken (Author) , Russell, Robert B. (Author)
Format: Article (Journal)
Language:English
Published: May 30, 2019
In: Cell
Year: 2019, Volume: 177, Issue: 7, Pages: 1933-1947.e25
ISSN:1097-4172
DOI:10.1016/j.cell.2019.04.044
Online Access:Verlag, Volltext: https://doi.org/10.1016/j.cell.2019.04.044
Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S0092867419304969
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Author Notes:Asuka Inoue, Francesco Raimondi, Francois Marie Ngako Kadji, Gurdeep Singh, Takayuki Kishi, Akiharu Uwamizu, Yuki Ono, Yuji Shinjo, Satoru Ishida, Nadia Arang, Kouki Kawakami, J. Silvio Gutkind, Junken Aoki, Robert B. Russell
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Summary:Summary - Heterotrimetic G proteins consist of four subfamilies (Gs, Gi/o, Gq/11, and G12/13) that mediate signaling via G-protein-coupled receptors (GPCRs), principally by receptors binding Gα C termini. G-protein-coupling profiles govern GPCR-induced cellular responses, yet receptor sequence selectivity determinants remain elusive. Here, we systematically quantified ligand-induced interactions between 148 GPCRs and all 11 unique Gα subunit C termini. For each receptor, we probed chimeric Gα subunit activation via a transforming growth factor-α (TGF-α) shedding response in HEK293 cells lacking endogenous Gq/11 and G12/13 proteins, and complemented G-protein-coupling profiles through a NanoBiT-G-protein dissociation assay. Interrogation of the dataset identified sequence-based coupling specificity features, inside and outside the transmembrane domain, which we used to develop a coupling predictor that outperforms previous methods. We used the predictor to engineer designer GPCRs selectively coupled to G12. This dataset of fine-tuned signaling mechanisms for diverse GPCRs is a valuable resource for research in GPCR signaling.
Item Description:Gesehen am 26.09.2019
Physical Description:Online Resource
ISSN:1097-4172
DOI:10.1016/j.cell.2019.04.044

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