Illuminating G-Protein-Coupling Selectivity of GPCRs
By A. Inoue, Francesco Raimondi, Francois Marie Ngako Kadji, Gurdeep Singh, Takayuki Kishi, Akiharu Uwamizu, Yuki Ono, Yuji Shinjo, S. Ishida, Nadia Arang and 4 more. 2019
548 citations recorded by the source corpus.
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.
Subfields: Cellular and Molecular Neuroscience, Molecular Biology
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The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Cellular and Molecular Neuroscience
- Albert J. Kooistra
- David E. Gloriam
- Gáspár Pándy-Szekeres
- Alibek Mamyrbekov
- György M. Keserü
- Christian Munk
- Stefan Mordalski
- Mauricio Esguerra
In Molecular Biology
- Albert J. Kooistra
- Gáspár Pándy-Szekeres
- David E. Gloriam
- Alibek Mamyrbekov
- György M. Keserü
- Christian Munk
- Stefan Mordalski
- Mauricio Esguerra
Citations in the corpus
- GPCRdb in 2021: integrating GPCR sequence, structure and function (2020, background): “cryo-electron microscopy (cryo-EM) (6), deep mutational scanning (7), genome sequencing (8) and signal protein profiling (9,10).”
- Structural insights into differences in G protein activation by family A and family B GPCRs (2020, methodology): “In this in vivo assay, an agonist-dependent decrease in signal was measured because of the receptor-mediated dissociation of the Gas and Gbg subunits (33).”