Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Cell, 2019-10, Vol.179 (4), p.895-908.e21

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2019

Link zum Volltext

Quelle

Elsevier ScienceDirect Journals Complete

Beschreibungen/Notizen

• 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. [Display omitted] [Display omitted] •Universal characteristics enabled prediction of peptide ligands and receptors•Multifaceted screening enabled detection of pathway- and assay-dependent responses•Peptide ligands discovered for BB3, GPR1, GPR15, GPR55, and GPR68•Each signaling system is a link to human physiology and is associated with disease 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.