Structural features and disease-associated functions of ADGRV1: insights from signaling mechanisms

Adhesion G protein-coupled receptor V1 (ADGRV1) is one of the largest and most modular receptors in the adhesion G protein-coupled receptor (aGPCR) family, integrating functions of cell adhesion, mechanosensing, and classical G protein signaling. Its structural domains, including calcium exchanger β (Calx-β) repeats, laminin G-like/ pentraxin (LamG/PTX) domain, epilepsy-associated (EPTP/EAR) repeats, GPCR-autoproteolysis-inducing (GAIN) domain/GPCR proteolytic site (GPS) module with tethered Stachel peptide, seven transmembrane (7TM) helices, and PDZ-binding motif (PBM), jointly shape its activation, intracellular transport, and effector coupling. Recent studies indicate that ADGRV1 exhibits context-dependent signaling, particularly through G protein coupling and ciliary localization, thereby influencing calcium homeostasis, autophagy, and developmental pathways. Genetic and functional evidence links ADGRV1 to Usher syndrome (USH) type II, epilepsy, and emerging associations with Alzheimer’s disease (AD), and recurrent somatic alterations in diverse cancers. Variants in ADGRV1 modulate processes such as ankle-link complex (ALC) assembly, synaptic stability, amyloid and tau regulation, chemoresistance, and immune microenvironment remodeling. Despite this progress, many aspects of its signaling mechanisms, ligand interactions, and disease relevance remain poorly understood. Future work combining high-resolution structural studies, systematic mapping of signaling bias, and rigorous translational validation will be essential to clarify the multifaceted roles of ADGRV1 and to evaluate its potential as a biomarker and therapeutic target. ADGRV1 is an unusually large protein found on the surface of many cells in the body. It acts like a sensor and communication hub, helping cells respond to their surroundings and send messages inside the cell. Because of its size and complex structure, ADGRV1 can perform several roles at once, including helping cells stick to each other, detect physical forces, and control internal signaling processes. Changes in the ADGRV1 have been linked to several human diseases, including Usher syndrome, which affects hearing and vision, certain forms of epilepsy, and possibly Alzheimer’s disease. Alterations in ADGRV1 have also been observed in some cancers. However, scientists still do not fully understand how changes in this single protein can lead to such different health problems. In this review, we have gathered the latest knowledge about how ADGRV1 is structured, how it is activated, and how it influences intracellular communication. Rather than focusing on only one pathway or disease, we look at the bigger picture and highlight common themes in how this protein works. We also discuss important unanswered questions and suggest directions for future research. A clearer understanding of ADGRV1 may help explain why it is involved in diverse diseases and could guide the development of new diagnostic tools or treatments in the future.