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bioRxiv · 10.1101/629576

Noncanonical scaffolding of Gαi and β-arrestin by G protein-coupled receptors

Smith, J. S.·Pack, T. F.·Inoue, A.·Lee, C.·Xiong, X.·Zheng, K.·Kahsai, A. W.·Choi, I.·Ma, Z.·Levitan, I. M.·Rochelle, L. K.·Staus, D. P.·Snyder, J. C.·Caron, M. G.·Rajagopal, S.
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Abstract

G-protein-coupled receptors (GPCRs) enable cells to sense and respond appropriately to hormonal and environmental signals, and are a target of ~30% of all FDA-approved medications. Canonically, each GPCR couples to distinct G proteins, such as Gs, Gi, Gq or G12/13, as well as {beta}-arrestins. These transducer proteins translate and integrate extracellular stimuli sensed by GPCRs into intracellular signals through what are broadly considered separable signalling pathways. However, the ability of G proteins to directly interact with {beta}-arrestins to integrate signalling has not previously been appreciated. Here we show a novel interaction between Gi protein family members and {beta}-arrestin. Gi:{beta}-arrestin complexes were formed by all GPCRs tested, regardless of their canonical G protein isoform coupling, and could bind both GPCRs as well as the extracellular signal-regulated kinase (ERK). This novel paradigm of Gi:{beta}-arrestin scaffolds enhances our understanding of GPCR signalling.

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Smith, J. S., Pack, T. F., Inoue, A., Lee, C., Xiong, X., Zheng, K., Kahsai, A. W., Choi, I., Ma, Z., Levitan, I. M., Rochelle, L. K., Staus, D. P., Snyder, J. C., Caron, M. G., Rajagopal, S.. 2019-05-07. Noncanonical scaffolding of Gαi and β-arrestin by G protein-coupled receptors. https://doi.org/10.1101/629576

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