Adhesion G protein-coupled receptors are activated by exposure of a cryptic tethered agonist.
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.
Departments of Pharmacology and Physiology and.
Hannah M
HM
Stoveken
Departments of Pharmacology and Physiology and.
Alexander G
AG
Hajduczok
Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642.
Lei
L
Xu
Departments of Pharmacology and Physiology and gregory_tall@urmc.rochester.edu.
Gregory G
GG
Tall
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002448:Cell Adhesion; D002460:Cell Line; D057809:HEK293 Cells; D006801:Humans; D007313:Insecta; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015513:Oncogene Proteins / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
C554449:ADGRF1 protein, human; C118925:ADGRG1 protein, human; D008024:Ligands; D015513:Oncogene Proteins; D010455:Peptides; D043562:Receptors, G-Protein-Coupled
G proteins; GPR110; GPR56; adhesion GPCRs; tethered agonist