Adhesion G Protein-Coupled Receptors as Drug Targets for Neurological Diseases

Abstract

The family of adhesion G protein-coupled receptors (aGPCRs) consists of 33 members in humans. Although the majority are orphan receptors with unknown functions, many reports have demonstrated critical functions for some members of this family in organogenesis, neurodevelopment, myelination, angiogenesis, and cancer progression. Importantly, mutations in several aGPCRs have been linked to human diseases. The crystal structure of a shared protein domain, the GPCR Autoproteolysis INducing (GAIN) domain, has enabled the discovery of a common signaling mechanism - a tethered agonist - for this class of receptors. A series of recent reports has shed new light on their biological functions and disease relevance. This review focuses on these recent advances in our understanding of aGPCR biology in the nervous system and the untapped potential of aGPCRs as novel therapeutic targets for neurological disease.

Keywords: GAIN domain; GPCR Autoproteolysis INducing domain; adhesion G protein-coupled receptors; neurodevelopment; neurological disease.

Figure 1:. Phylogenetic organization, domain structure, and G protein coupling of human adhesion GPCR subfamilies I-IX.

The left inset shows the GAIN domain crystal structure of rat latrophilin with subdomain A (yellow) and subdomain B (magenta), modified from [111]. The right inset identifies general domains and features of aGPCRs. All human aGPCRs are phylogenetically clustered by homology in the center ring, with gene names, aliases, and aGPCR families listed in the middle ring. G protein-coupling, when known, is illustrated in the outer ring, with the corresponding aGPCR structure and protein domains (not to scale). Receptor homology and phylogenetic clustering was performed by GPCRdb (accessed 3/19/2018). Receptor domains were determined by the NCBI Conserved Domain calculator (accessed 3/19/2018), the UniProt database (accessed 3/19/2018), and published reports. G protein coupling was determined by the Guide To Pharmacology (IUPHAR/BPS; accessed 3/19/2018) and published reports [, –114]. Abbreviations used: ECD: extracellular domain; 7TM: seven transmembrane domain; ICD: intracellular domain; NTF: N-terminal fragment; GAIN: GPCR autoproteolytic-inducing domain; CTF: C-terminal domain; IgG: immunoglobulin G; Leu-rich: leucine-rich; EAR: epilepsy-associated repeat; Calx: calcium exchanger; EGF: epidermal growth factor-like domain; LamG/PTX: laminin G/pentraxin; TSP: thrombospondin repeat; CUB: complement C1r/C1s, Uegf, Bmp1; SEA: sperm protein/enterokinase/agrin; PLL: pentraxin (PTX)/laminin/neurexin/sex-hormone-binding globulin (LNS)-like; GBL: galactose-binding lectin; HRM: hormone motif; EGF (Ca²⁺): calcium-binding EGF domain.

Figure 2:. Three proposed models of aGPCR activation.

(A) In the first model, NTF and N-terminal GAIN domains conceal the conserved, cryptic tethered agonist Stachel structure in the CTF. Binding of extracellular ligand, possibly combined with mechanical force, removes the NTF, thereby exposing the Stachel structure, which interacts with extracellular loops of the 7TM domain and initiates conformational changes leading to constitutive downstream G protein signaling. (B) In the second model, ligand binding induces conformational changes independent of Stachel structure exposure, leading to transient and reversible downstream G protein signaling. (C) In the third model, ligand binding induced conformational changes that result in exposure of the Stachel structure and Stachel-dependent, potentially transient downstream signaling mediated through the 7TM.

Figure 3:. Domain-specific functions of ADGRG6.

The NTF attachment of ADGRG6 to its CTF suppresses receptor activity, thereby maintaining Schwann cells in an immature state and allowing for radial sorting of cells to axons. Increased accumulation and binding of its ligand laminin-211 removes the NTF, thereby allowing for Stachel-dependent activation of ADGRG6, association with G_αs, accumulation of cyclic AMP (cAMP), and the initiation of cAMP-dependent myelinogenic gene programs and the myelination of peripheral axons. Adapted from [30].

Figure 4:. Splice variants of ADGRG1.

(A) Gene structure of human full-length (FL) ADGRG1 and related isoforms S1-S4. The corresponding protein domains are shown below. Adapted from [32]. (B). Crystal structure of the extracellular domain of ADGRG1 in complex with α5 (orange). Disulfide bonds in yellow, linker in pink. PLL and GAIN domain in cyan and grey, respectively. Modified from [34]. (C). Schematic of ADGRG1 with same color-coding as C. The single yellow line indicating two disulfide bonds between PLL and GAIN domains. (D). Schematic of S4 isoform of ADGRG1.