Mechanisms of adhesion G protein–coupled receptor activation

Maiya Yu,Jennifer Yeung,Alexander Vizurraga,Rashmi Adhikari,Gregory G. Tall

doi:10.1074/jbc.rev120.007423

Abstract

Adhesion G protein-coupled receptors (AGPCRs) are a thirty-three-member subfamily of Class B GPCRs that control a wide array of physiological processes and are implicated in disease. AGPCRs uniquely contain large, self-proteolyzing extracellular regions that range from hundreds to thousands of residues in length. AGPCR autoproteolysis occurs within the extracellular GPCR autoproteolysis-inducing (GAIN) domain that is proximal to the N terminus of the G protein-coupling seven-transmembrane-spanning bundle. GAIN domain-mediated self-cleavage is constitutive and produces two-fragment holoreceptors that remain bound at the cell surface. It has been of recent interest to understand how AGPCRs are activated in relation to their two-fragment topologies. Dissociation of the AGPCR fragments stimulates G protein signaling through the action of the tethered-peptide agonist stalk that is occluded within the GAIN domain in the holoreceptor form. AGPCRs can also signal independently of fragment dissociation, and a few receptors possess GAIN domains incapable of self-proteolysis. This has resulted in complex theories as to how these receptors are activated in vivo, complicating pharmacological advances. Currently, there is no existing structure of an activated AGPCR to support any of the theories. Further confounding AGPCR research is that many of the receptors remain orphans and lack identified activating ligands. In this review, we provide a detailed layout of the current theorized modes of AGPCR activation with discussion of potential parallels to mechanisms used by other GPCR classes. We provide a classification means for the ligands that have been identified and discuss how these ligands may activate AGPCRs in physiological contexts.

Highlights

G protein–coupled receptors (GPCRs) are the largest class of membrane receptors, comprising over 800 members in humans
There has yet to be a report of a hormone that binds to an adhesion GPCRs (AGPCRs), leading many to believe that the hormone receptor (HormR) domain has additional functions beyond hormone binding (Fig. 1E) [10]
The C-terminal ends of longer peptides may be necessary for proper folding or bending about the predicted turn element to accommodate binding to the AGPCR orthosteric site, whereas the 7-mer ADGRG1 peptide may be a rare perfect fit that requires only the core tethered agonist sequence

Summary

The unique structural topology of adhesion GPCRs

The 33 human adhesion GPCRs (ADGRs) are divided among nine subfamilies, ADGRA–G, -L, and -V, based on sequence similarity [6, 7]. There has yet to be a report of a hormone that binds to an AGPCR, leading many to believe that the HormR domain has additional functions beyond hormone binding (Fig. 1E) [10] Another interesting motif found in select adhesion GPCR ECRs is the sperm protein, enterokinase, and agrin (SEA) domain. The stalk that connects TM1 to the GAIN domain and includes b-strand 13 has been named the adhesion GPCR tethered-peptide agonist ( referred to as the tethered agonist) This conserved sequence within multiple AGPCRs was shown independently by two groups to play a pivotal role in mediating receptor activation [21, 22]. Noncleaved AGPCRs are still capable of signaling, leaving open the question of how these receptors become activated

Adhesion GPCR activation mechanisms

Allosteric activation and inhibition

How do AGPCR ligands modulate receptor activity?

Unknown ligand on macrophages and neutrophils

Extracellular matrix ligands

Soluble extracellular ligands

Conclusions