A spatiotemporally resolved GPCR interactome reveals novel mediators of receptor agonism

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A spatiotemporally resolved GPCR interactome reveals novel mediators of receptor agonism

Authors

Shchepinova, M. M.; Richardson, R.; Houghton, J. W.; Walker, A. R.; Conole, D.; Hanyaloglu, A. C.; Tate, E. W.

Abstract

Cellular signaling by membrane G protein-coupled receptors (GPCRs) is orchestrated by a complex and diverse array of mechanisms. The dynamics of a GPCR interactome as it evolves over time and space in response to an agonist can offer a unique window on pleiotropic signaling decoding and functional selectivity at a cellular level. In this study, we employed proximity-based APEX2 proteomics to interrogate the interaction network of the GPCR for luteinizing hormone (LHR) on a sub-minute timescale. We developed an analytical approach integrating quantitative multiplexed proteomics and temporal reference profiles, providing a platform to identify the proteomic environment of APEX2-tagged LHR at the nanometer scale. LHR activity is exquisitely regulated at a spatial level, leading to identification of novel interactors including the Ras-related GTPase RAP2B that modulate both receptor signaling and post-endocytic trafficking, and providing a resource for spatiotemporal nanodomain mapping of LHR interactors across subcellular compartments.

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