Discovery of Human Signaling Systems

Pairing Peptides to G Protein-Coupled Receptors

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

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)895-908
Number of pages14
JournalCell
Volume179
Issue number4
DOIs
Publication statusPublished - 31 Oct 2019

Keywords

  • deorphanization
  • endogenous ligand
  • evolution
  • genomics
  • GPCR
  • machine learning
  • orphan receptor
  • peptide ligand
  • pharmacological screening
  • receptor internalization

Cite this

Foster, S. R., Hauser, A. S., Vedel, L., Strachan, R. T., Huang, X. P., Gavin, A. C., ... Gloriam, D. E. (2019). Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors. Cell, 179(4), 895-908. https://doi.org/10.1016/j.cell.2019.10.010
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. / Discovery of Human Signaling Systems : Pairing Peptides to G Protein-Coupled Receptors. In: Cell. 2019 ; Vol. 179, No. 4. pp. 895-908.
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title = "Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors",
abstract = "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.",
keywords = "deorphanization, endogenous ligand, evolution, genomics, GPCR, machine learning, orphan receptor, peptide ligand, pharmacological screening, receptor internalization",
author = "Foster, {Simon R.} and Hauser, {Alexander S.} and Line Vedel and Strachan, {Ryan T.} and Huang, {Xi Ping} and Gavin, {Ariana C.} and Shah, {Sushrut D.} and Nayak, {Ajay P.} and Haugaard-Kedstr{\"o}m, {Linda M.} and Penn, {Raymond B.} and Roth, {Bryan L.} and Hans Br{\"a}uner-Osborne and Gloriam, {David E.}",
year = "2019",
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pages = "895--908",
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Foster, SR, Hauser, AS, Vedel, L, Strachan, RT, Huang, XP, Gavin, AC, Shah, SD, Nayak, AP, Haugaard-Kedström, LM, Penn, RB, Roth, BL, Bräuner-Osborne, H & Gloriam, DE 2019, 'Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors', Cell, vol. 179, no. 4, pp. 895-908. https://doi.org/10.1016/j.cell.2019.10.010

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

In: Cell, Vol. 179, No. 4, 31.10.2019, p. 895-908.

Research output: Contribution to journalArticleResearchpeer-review

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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.

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.

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KW - evolution

KW - genomics

KW - GPCR

KW - machine learning

KW - orphan receptor

KW - peptide ligand

KW - pharmacological screening

KW - receptor internalization

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U2 - 10.1016/j.cell.2019.10.010

DO - 10.1016/j.cell.2019.10.010

M3 - Article

VL - 179

SP - 895

EP - 908

JO - Cell

JF - Cell

SN - 0092-8674

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