Role of Adhesion G Protein-Coupled Receptors in Immune Dysfunction and Disorder

Adhesion G protein-coupled receptors (aGPCRs) make up the second-largest GPCR subfamily which comprises a total of 33 different members in humans [1]. Several distinctive structural and functional characteristics of aGPCRs set them apart from other GPCRs. The N-terminal extracellular region of aGPCRs is markedly large and comprises many different cell-adhesive protein motifs arranged in tandem or in mixed combination. These protein motifs, including the epidermal growth factor (EGF)-, immunoglobulin (Ig)-, lectin-, leucine-rich repeat (LRR)-, pentraxin (PTX)-, thrombospondin (TSP)-like, and hormone-binding domains, all have well-known protein–protein interaction and cellular adhesion functions. A hallmark GPCR autoproteolysis-inducing (GAIN) domain is located immediately after the cell-adhesive protein motifs and before the signature seven-transmembrane (7TM) domain (Figure 1). These structural features stipulate bilateral extracellular adhesion and intracellular signaling functions for aGPCRs. Indeed, diverse ligands/interacting partners of endogenous and exogenous origins, including soluble, cell surface, and cell matrix proteins, carbohydrates, lipids, and microbial products have been identified for aGPCRs. In addition, both G protein-dependent and -independent signaling pathways were known to be induced by aGPCRs.