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Conformational plasticity of the intracellular cavity of GPCR-G-protein complexes leads to G-protein promiscuity and selectivity.


ABSTRACT: 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 G?s, G?i, and G?q 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 ?2-adrenergic receptor stabilize binding of noncognate G?q protein in its latent cavity, allowing promiscuous signaling through both G?s and G?q 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.

SUBMITTER: Sandhu M 

PROVIDER: S-EPMC6575595 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Conformational plasticity of the intracellular cavity of GPCR-G-protein complexes leads to G-protein promiscuity and selectivity.

Sandhu Manbir M   Touma Anja M AM   Dysthe Matthew M   Sadler Fredrik F   Sivaramakrishnan Sivaraj S   Vaidehi Nagarajan N  

Proceedings of the National Academy of Sciences of the United States of America 20190528 24


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 Gα<sub>s</sub>, Gα<sub>i</sub>, and Gα<sub>q</sub> proteins assume a small ensemble of unique orie  ...[more]

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