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Conformational plasticity of the intracellular cavity of GPCR–G-protein complexes leads to G-protein promiscuity and selectivity
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Conformational plasticity of the intracellular cavity of GPCR–G-protein complexes leads to G-protein promiscuity and selectivity
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Journal Article
Conformational plasticity of the intracellular cavity of GPCR–G-protein complexes leads to G-protein promiscuity and selectivity
2019
Overview
While the dynamics of the intracellular surface in agonist-stimulated GPCRs is well studied, the impact of GPCR dynamics on G-protein selectivity remains unclear. Here, we combine molecular dynamics simulations with live-cell FRET and secondary messenger measurements, for 21 GPCR–G-protein combinations, to advance a dynamic model of the GPCR–G-protein interface. Our data show C terminus peptides of Gαs, Gαi, and Gαq proteins assume a small ensemble of unique orientations when coupled to their cognate GPCRs, similar to the variations observed in 3D structures of GPCR–G-protein complexes. The noncognate G proteins interface with latent intracellular GPCR cavities but dissociate due to weak and unstable interactions. Three predicted mutations in β₂-adrenergic receptor stabilize binding of noncognate Gαq protein in its latent cavity, allowing promiscuous signaling through both Gαs and Gαq in a dose-dependent manner. This demonstrates that latent GPCR cavities can be evolved, by design or nature, to tune G-protein selectivity, giving insights to pluridimensional GPCR signaling.
Publisher
National Academy of Sciences
Subject
/ Biophysics and Computational Biology
/ Cavities
/ Fluorescence resonance energy transfer
/ GTP-Binding Protein alpha Subunits, Gq-G11 - metabolism
/ GTP-Binding Proteins - metabolism
/ Holes
/ Humans
/ Mutation
/ Peptides
/ Protein Binding - physiology
/ Proteins
/ Receptors, G-Protein-Coupled - metabolism
