Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors.
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.
['Foster|Simon R|SR|', 'Hauser|Alexander S|AS|', 'Vedel|Line|L|', 'Strachan|Ryan T|RT|', 'Huang|Xi-Ping|XP|', 'Gavin|Ariana C|AC|', 'Shah|Sushrut D|SD|', 'Nayak|Ajay P|AP|', 'Haugaard-Kedström|Linda M|LM|', 'Penn|Raymond B|RB|', 'Roth|Bryan L|BL|', 'Bräuner-Osborne|Hans|H|', 'Gloriam|David E|DE|']
D000595:Amino Acid Sequence D019295:Computational Biology D053263:Gene Regulatory Networks D005835:Genitalia D023281:Genomics D006801:Humans D008024:Ligands D009369:Neoplasms D009422:Nervous System Diseases D010455:Peptides D011487:Protein Conformation D043562:Receptors, G-Protein-Coupled D015398:Signal Transduction
GPCR genomics endogenous ligand deorphanization evolution machine learning orphan receptor peptide ligand pharmacological screening receptor internalization