Adhesion G Protein-Coupled Receptors as Drug Targets

Abstract

The adhesion G protein-coupled receptors (aGPCRs) are an evolutionarily ancient family of receptors that play key roles in many different physiological processes. These receptors are notable for their exceptionally long ectodomains, which span several hundred to several thousand amino acids and contain various adhesion-related domains, as well as a GPCR autoproteolysis-inducing (GAIN) domain. The GAIN domain is conserved throughout almost the entire family and undergoes autoproteolysis to cleave the receptors into two noncovalently-associated protomers. Recent studies have revealed that the signaling activity of aGPCRs is largely determined by changes in the interactions among these protomers. We review recent advances in understanding aGPCR activation mechanisms and discuss the physiological roles and pharmacological properties of aGPCRs, with an eye toward the potential utility of these receptors as drug targets.

Keywords: agonist; antagonist; antibody; ligand; pharmaceutical; therapeutic.

Figure 1.. Adhesion GPCR sub-family structures.

The 9 adhesion GPCR sub-families are listed alphabetically with key protein domains depicted for each group. Some sub-family members have a slightly different structure from what is indicated in the figure: ADGRA1-No GAIN, HRM, IG, LRR; ADGRA2-No Ig; ADGRB3 has NT CUB but no Pro; ADGRB1–5xTSP1; ADGRC1 and C3 no Pro; ADGRF2–4 no SEA; ADGRG1–7: G1-PLL, G6-CUB, Laminin, PBM only in G1; ADGRL1–4: Pro only in L1, L4-Only EGF and GAIN. Abbreviations: GAIN: GPCR autoproteolysis-inducing domain; LRR: Leucine-rich repeat; Ig: Immunoglobulin-like; HRM: Hormone receptor motif; TSP: Type-1 thrombospondin repeat; Cad: Cadherin repeat; EGF: Epidermal Growth Factor-like (includes Calcium-binding EGF-like domains); Lam: Laminin; Pro: polyproline sequence; PBM: PDZ binding motif; SEA: Sperm protein/Enterokinase/Agrin domain; RBL: rhammose-binding lectin; OLMD; olfactomedin-like; EAR: Epilepsy-associated repeat.

Figure 2.. Models of the activation of adhesion GPCR signaling.

Generally speaking, adhesion GPCR activation is governed by interactions between the N-terminal fragment (NTF) and C-terminal fragment (CTF) protomers. A) The tethered agonist (e.g. stalk, stachel) can be unmasked when the NTF is completely removed. B) The stalk may also act as a lever, with its position being modulated by NTF movements to tune receptor activity. C) The NTF can also in some cases suppress signaling by the CTF protomer in ways that do not depend on the stalk, with disinhibition being achieved when the NTF is pulled away from the CTF by ligand interactions or shed completely from the protein complex. It should be noted that these mechanisms are not mutually exclusive, and in fact all three mechanisms may occur for any given aGPCR, although the relative importance of each mechanism may vary from receptor to receptor.

Figure 3.. Adhesion GPCR signaling pathways.

Adhesion GPCRs have been found to initiate a wide variety of downstream signaling cascades. This schematic diagram summarizes signaling pathways for which there is presently evidence of activation by more than one aGPCR.

Figure 4.. Targeting adhesion GPCRs with therapeutics.

Adhesion GPCRs offer many opportunities for targeted drug development, including i) small molecule agonists, antagonists or allosteric modulators (red), ii) peptides or peptidomimetic agonists (purple) that act at the tethered agonist interaction site, iii) modulators of GAIN proteolysis (green), iv) antibodies that modulate receptor activity (dark blue), and v) regulators of protein-protein interactions both extracellularly (orange) and intracellularly, for example with small molecules that disrupt binding to PDZ scaffold proteins (light blue).