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EnglishHeterotrimetic 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.
| Titolo: | Illuminating G-Protein-Coupling Selectivity of GPCRs | |
| Autori: | ||
| Data di pubblicazione: | 2019 | |
| Rivista: | ||
| Digital Object Identifier (DOI): | http://dx.doi.org/10.1016/j.cell.2019.04.044 | |
| Parole Chiave: | bioinformatics; chimeric G protein; DREADD; G-protein-coupled receptors; HEK293 cells; NanoBiT; prediction; protein design; signaling; TGF-α shedding assay | |
| Handle: | http://hdl.handle.net/11384/81722 | |
| Appare nelle tipologie: | 1.1 Articolo in rivista |
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