ArticleThe Journal of biological chemistry2015
Pivotal role of extended linker 2 in the activation of Gα by G protein-coupled receptor.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
What it found
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Who cites it
9 citing papers in PubMed, 9 citations in OpenAlex.
- Structural insights into single-pass transmembrane receptor GC-A activation by distinct antihypertensive antibodies.Nature communications · 2026Article
- Architecture and activation of single-pass transmembrane receptor guanylyl cyclase.Nature structural & molecular biology · 2025Article
- Distinct binding conformations of epinephrine with α- and β-adrenergic receptors.Experimental & molecular medicine · 2024Article
- Structures of βNature communications · 2022Article
- Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate.Nature communications · 2022Article
- Structural Basis of the Activation of Heterotrimeric Gs-Protein by Isoproterenol-Bound βMolecular cell · 2020Article
- BetaBiochimica et biophysica acta. Biomembranes · 2017Article
- Regulation, Signaling, and Physiological Functions of G-Proteins.Journal of molecular biology · 2016Review
- Quantifying conformational changes in GPCRs: glimpse of a common functional mechanism.BMC bioinformatics · 2015Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
G protein-coupled receptors (GPCRs) relay extracellular signals mainly to heterotrimeric G-proteins (Gαβγ) and they are the most successful drug targets. The mechanisms of G-protein activation by GPCRs are not well understood. Previous studies have revealed a signal relay route from a GPCR via the C-terminal α5-helix of Gα to the guanine nucleotide-binding pocket. Recent structural and biophysical studies uncover a role for the opening or rotating of the α-helical domain of Gα during the activation of Gα by a GPCR. Here we show that β-adrenergic receptors activate eight Gαs mutant proteins (from a screen of 66 Gαs mutants) that are unable to bind Gβγ subunits in cells. Five of these eight mutants are in the αF/Linker 2/β2 hinge region (extended Linker 2) that connects the Ras-like GTPase domain and the α-helical domain of Gαs. This extended Linker 2 is the target site of a natural product inhibitor of Gq. Our data show that the extended Linker 2 is critical for Gα activation by GPCRs. We propose that a GPCR via its intracellular loop 2 directly interacts with the β2/β3 loop of Gα to communicate to Linker 2, resulting in the opening and closing of the α-helical domain and the release of GDP during G-protein activation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.