Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors

Research output: Contribution to journalJournal articleResearchpeer-review

Simon R Foster, Alexander S Hauser, Line Vedel, Ryan T Strachan, Xi-Ping Huang, Ariana C Gavin, Sushrut D Shah, Ajay P Nayak, Linda M Haugaard-Kedström, Raymond B Penn, Bryan L Roth, Hans Bräuner-Osborne, David E Gloriam

The peptidergic system is the most abundant network of ligand-receptor-mediated signaling in humans. However, the physiological roles remain elusive for numerous peptides and more than 100 G protein-coupled receptors (GPCRs). Here we report the pairing of cognate peptides and receptors. Integrating comparative genomics across 313 species and bioinformatics on all protein sequences and structures of human class A GPCRs, we identify universal characteristics that uncover additional potential peptidergic signaling systems. Using three orthogonal biochemical assays, we pair 17 proposed endogenous ligands with five orphan GPCRs that are associated with diseases, including genetic, neoplastic, nervous and reproductive system disorders. We also identify additional peptides for nine receptors with recognized ligands and pathophysiological roles. This integrated computational and multifaceted experimental approach expands the peptide-GPCR network and opens the way for studies to elucidate the roles of these signaling systems in human physiology and disease. VIDEO ABSTRACT.

Original languageEnglish
JournalCell
Volume179
Issue number4
Pages (from-to)895-908
ISSN0092-8674
DOIs
Publication statusPublished - 31 Oct 2019

Bibliographical note

Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

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