Profiling the proximal proteome of the activated μ-opioid receptor.

The μ-opioid receptor (μOR) represents an important target of therapeutic and abused drugs. So far, most understanding of μOR activity has focused on a subset of known signal transducers and regulatory molecules. Yet μOR signaling is coordinated by additional proteins in the interaction network of the activated receptor, which have largely remained invisible given the lack of technologies to interrogate these networks systematically. Here we describe a proteomics and computational approach to map the proximal proteome of the activated μOR and to extract subcellular location, trafficking and functional partners of G-protein-coupled receptor (GPCR) activity. We demonstrate that distinct opioid agonists exert differences in the μOR proximal proteome mediated by endocytosis and endosomal sorting. Moreover, we identify two new μOR network components, EYA4 and KCTD12, which are recruited on the basis of receptor-triggered G-protein activation and might form a previously unrecognized buffering system for G-protein activity broadly modulating cellular GPCR signaling. © 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.

Citation

Benjamin J Polacco, Braden T Lobingier, Emily E Blythe, Nohely Abreu, Prachi Khare, Matthew K Howard, Alberto J Gonzalez-Hernandez, Jiewei Xu, Qiongyu Li, Brandon Novy, Zun Zar Chi Naing, Brian K Shoichet, Willow Coyote-Maestas, Joshua Levitz, Nevan J Krogan, Mark Von Zastrow, Ruth Hüttenhain. Profiling the proximal proteome of the activated μ-opioid receptor. Nature chemical biology. 2024 Sep;20(9):1133-1143

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PMID: 38528119

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