Tethered agonists: a new mechanism underlying adhesion G protein-coupled receptor activation

J Recept Signal Transduct Res. 2015 Jun;35(3):220-3. doi: 10.3109/10799893.2015.1072978. Epub 2015 Sep 14.


The family of adhesion G protein-coupled receptors (aGPCRs) comprises 33 members in the human genome, which are subdivided into nine subclasses. Many aGPCRs undergo an autoproteolytic process via their GPCR Autoproteolysis-INducing (GAIN) domain during protein maturation to generate an N- and a C-terminal fragments, NTF and CTF, respectively. The NTF and CTF are non-covalently reassociated on the plasma membrane to form a single receptor unit. How aGPCRs are activated upon ligand binding remains one of the leading questions in the field of aGPCR research. Recent work from our labs and others shows that ligand binding can remove the NTF from the plasma membrane-bound CTF, exposing a tethered agonist which potently activates downstream signaling.

Keywords: G protein-coupled signaling; adhesion GPCR; tethered agonist.

Publication types

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

MeSH terms

  • Animals
  • Cell Adhesion Molecules / chemistry*
  • Cell Adhesion Molecules / physiology*
  • Cell Adhesion Molecules / ultrastructure
  • Computer Simulation
  • Humans
  • Membrane Proteins / chemistry*
  • Membrane Proteins / physiology*
  • Membrane Proteins / ultrastructure
  • Models, Biological
  • Models, Chemical
  • Receptors, G-Protein-Coupled / chemistry*
  • Receptors, G-Protein-Coupled / physiology*
  • Receptors, G-Protein-Coupled / ultrastructure
  • Structure-Activity Relationship


  • Cell Adhesion Molecules
  • Membrane Proteins
  • Receptors, G-Protein-Coupled