Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist

Proc Natl Acad Sci U S A. 2015 May 12;112(19):6194-9. doi: 10.1073/pnas.1421785112. Epub 2015 Apr 27.

Abstract

The large class of adhesion G protein-coupled receptors (aGPCRs) bind extracellular matrix or neighboring cell-surface ligands to regulate organ and tissue development through an unknown activation mechanism. We examined aGPCR activation using two prototypical aGPCRs, GPR56 and GPR110. Active dissociation of the noncovalently bound GPR56 or GPR110 extracellular domains (ECDs) from the respective seven-transmembrane (7TM) domains relieved an inhibitory influence and permitted both receptors to activate defined G protein subtypes. After ECD displacement, the newly revealed short N-terminal stalk regions of the 7TM domains were found to be essential for G protein activation. Synthetic peptides comprising these stalks potently activated GPR56 or GPR110 in vitro or in cells, demonstrating that the stalks comprise a tethered agonist that was encrypted within the ECD. Establishment of an aGPCR activation mechanism provides a rational platform for the development of aGPCR synthetic modulators that could find clinical utility toward aGPCR-directed disease.

Keywords: G proteins; GPR110; GPR56; adhesion GPCRs; tethered agonist.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cell Adhesion
  • Cell Line
  • HEK293 Cells
  • Humans
  • Insecta
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • Oncogene Proteins / metabolism*
  • Peptides / chemistry
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, G-Protein-Coupled / metabolism*
  • Sequence Homology, Amino Acid
  • Signal Transduction

Substances

  • ADGRF1 protein, human
  • ADGRG1 protein, human
  • Ligands
  • Oncogene Proteins
  • Peptides
  • Receptors, G-Protein-Coupled