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

TY - JOUR

T1 - Discovery of Human Signaling Systems

T2 - Pairing Peptides to G Protein-Coupled Receptors

AU - Foster, Simon R

AU - Hauser, Alexander S

AU - Vedel, Line

AU - Strachan, Ryan T

AU - Huang, Xi-Ping

AU - Gavin, Ariana C

AU - Shah, Sushrut D

AU - Nayak, Ajay P

AU - Haugaard-Kedström, Linda M

AU - Penn, Raymond B

AU - Roth, Bryan L

AU - Bräuner-Osborne, Hans

AU - Gloriam, David E

N1 - Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2019/10/31

Y1 - 2019/10/31

N2 - 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: Features learned from comparative sequence and structural analyses enabled prediction of peptide ligands for orphan GPCRs that, when coupled with functional validation, expose physiologically relevant signaling systems.

AB - 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: Features learned from comparative sequence and structural analyses enabled prediction of peptide ligands for orphan GPCRs that, when coupled with functional validation, expose physiologically relevant signaling systems.

U2 - 10.1016/j.cell.2019.10.010

DO - 10.1016/j.cell.2019.10.010

M3 - Journal article

C2 - 31675498

SN - 0092-8674

VL - 179

SP - 895

EP - 908

JO - Cell

JF - Cell

IS - 4

ER -