Adhesion GPCRs

Over 800 genes constituting ~3% of the human genome encode the largest family of cell surface integral membrane proteins called G Protein coupled receptors (GPCRs). GPCRs mediate sensing large assortment of extracellular signals such as hormones, ions, neurotransmitters, mechanical stimuli even light and transmitting them inside the cell. As a result of their leading roles in numerous important biological systems and wide variety of indications including neurodegenerative, cardiovascular, metabolic, infectious, oncologic diseases and neurological disorders; GPCRs are the target of ~40% of currently marketed drugs. Hence, keeping them continuously in the focus of scientists, clinicians and pharmaceutical companies.

Adhesion GPCRs (aGPCRs) constitute the second largest and possibly the coolest class of GPCR family. They are present in most animals as well as in some primitive unicellular eukaryotes and evolutionary conserved, yet aGPCRs still remain to be the least understood among other receptor families. In humans, 33 aGPCRs have been identified, nevertheless numerous splice variants contribute to a bigger variety with potential implications in signal transduction. Adhesion GPCRs have significant physiological roles in brain development, cell polarity in neural development, central nervous system angiogenesis, male infertility, immunity and important pathological roles in cancer, bilateral frontoparietal polymicrogyria (BFPP), Usher syndrome 2, attention-deficit/hyperactivity disorder and polycystic kidney disease. They are expressed in various parts of the human body and involved in the development. Altogether these findings point out that aGPCRs represent a class of potentially important drug targets. Hence, understanding their mechanisms of activation, interactome and elucidating the downstream signaling pathways will provide insights with the potential to lead novel therapeutic agents.

Adhesion GPCRs have large N-terminal fragment (NTF) that carry multiple functional domains including the conserved GAIN domain. Intriguingly, aGPCRs are auto-proteolytically cleaved from the conserved GPS site on the GAIN domain into NTF and C-terminal fragment (CTF) which is composed of a Stachel/stalk domain + 7-transmembrane domain (7TM). However, these heterodimeric structure stay non-covalently bound and display classic hallmarks of GPCR signal transduction. Both NTF and Stachel/stalk domain on the CTF is known to contribute modes of signaling, yet their roles, interaction between these domains and conformational changes during the signaling remain unknown.