ADGRV1的结构特征与疾病相关功能：来自信号机制的见解

文献信息

中文摘要

黏附G蛋白偶联受体V1（ADGRV1）是黏附G蛋白偶联受体（aGPCR）家族中最大且模块化程度最高的受体之一，整合了细胞黏附、机械感知和经典G蛋白信号传导的功能。其结构域包括钙交换体β（Calx-β）重复序列、层粘连蛋白G样/五聚蛋白（LamG/PTX）结构域、癫痫相关（EPTP/EAR）重复序列、GPCR自蛋白水解诱导（GAIN）结构域/GPCR蛋白水解位点（GPS）模块及系留Stachel肽、七次跨膜（7TM）螺旋和PDZ结合基序（PBM），共同塑造其激活、细胞内运输和效应器偶联。近期研究表明，ADGRV1表现出情境依赖性信号传导，尤其是通过G蛋白偶联和纤毛定位，从而影响钙稳态、自噬和发育通路。遗传学和功能学证据将ADGRV1与Usher综合征（USH）II型、癫痫联系起来，并新近发现其与阿尔茨海默病（AD）以及多种癌症中的反复体细胞改变相关。ADGRV1变异可调节踝连接复合体（ALC）组装、突触稳定性、淀粉样蛋白和tau调控、化疗耐药及免疫微环境重塑等过程。尽管取得了这些进展，其信号机制、配体相互作用和疾病相关性的许多方面仍知之甚少。未来的工作需结合高分辨率结构研究、信号偏倚的系统性图谱绘制和严格的转化验证，以阐明ADGRV1的多方面作用并评估其作为生物标志物和治疗靶点的潜力。

英文摘要

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.