GPCRs globally coevolved with receptor activity-modifying proteins, RAMPs

Proceedings of the National Academy of Sciences of the United States of America
Shahar BarbashThomas P Sakmar

Abstract

Receptor activity-modifying proteins (RAMPs) are widely expressed in human tissues and, in some cases, have been shown to affect surface expression or ligand specificity of G-protein-coupled receptors (GPCRs). However, whether RAMP-GPCR interactions are widespread, and the nature of their functional consequences, remains largely unknown. In humans, there are three RAMPs and over 800 expressed GPCRs, making direct experimental approaches challenging. We analyzed relevant genomic data from all currently available sequenced organisms. We discovered that RAMPs and GPCRs tend to have orthologs in the same species and have correlated phylogenetic trees to the same extent, or higher than other interacting protein pairs that play key roles in cellular signaling. In addition, the resulting RAMP-GPCR interaction map suggests that RAMP1 and RAMP3 interact with the same set of GPCRs, which implies functional redundancy. We next analyzed human transcriptomes and found expression correlation for GPCRs and RAMPs. Our results suggest global coevolution of GPCRs and RAMPS and support the hypothesis that GPCRs interact globally with RAMPs in cellular signaling pathways.

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Citations

Sep 27, 2019·Science Advances·Emily LorenzenThomas P Sakmar
Sep 14, 2018·Nature·Yi-Lynn LiangPatrick M Sexton
Aug 15, 2018·Nature Reviews. Molecular Cell Biology·Denise WoottenPatrick M Sexton
Nov 13, 2019·Proceedings of the National Academy of Sciences of the United States of America·Duncan I MackieKathleen M Caron
Feb 6, 2019·Journal of Medicinal Chemistry·Quinn CoughlinDario Doller
Apr 23, 2018·ACS Pharmacology & Translational Science·Rebekah L BowerDebbie L Hay
Aug 25, 2020·ACS Pharmacology & Translational Science·Paris AvgoustouGareth O Richards

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