Department of Genetics and Cell Physiology, University of Wrocław, Kanonia 6/8, 50-328 Wrocław, Poland.
Int J Mol Sci. 2022 Apr 30;23(9):4988. doi: 10.3390/ijms23094988.
α-Arrestins, also called arrestin-related trafficking adaptors (ARTs), constitute a large family of proteins conserved from yeast to humans. Despite their evolutionary precedence over their extensively studied relatives of the β-arrestin family, α-arrestins have been discovered relatively recently, and thus their properties are mostly unexplored. The predominant function of α-arrestins is the selective identification of membrane proteins for ubiquitination and degradation, which is an important element in maintaining membrane protein homeostasis as well as global cellular metabolisms. Among members of the arrestin clan, only α-arrestins possess PY motifs that allow canonical binding to WW domains of Rsp5/NEDD4 ubiquitin ligases and the subsequent ubiquitination of membrane proteins leading to their vacuolar/lysosomal degradation. The molecular mechanisms of the selective substrate's targeting, function, and regulation of α-arrestins in response to different stimuli remain incompletely understood. Several functions of α-arrestins in animal models have been recently characterized, including redox homeostasis regulation, innate immune response regulation, and tumor suppression. However, the molecular mechanisms of α-arrestin regulation and substrate interactions are mainly based on observations from the yeast model. Nonetheless, α-arrestins have been implicated in health disorders such as diabetes, cardiovascular diseases, neurodegenerative disorders, and tumor progression, placing them in the group of potential therapeutic targets.
α- arrestins，也称为 arrestin 相关转运适配器 (ARTs)，是从酵母到人都保守的一大类蛋白质家族。尽管它们的进化先于广泛研究的β-arrestin 家族，但α-arrestins 是最近才被发现的，因此它们的特性大多尚未被探索。α-arrestins 的主要功能是选择性识别膜蛋白进行泛素化和降解，这是维持膜蛋白内稳态以及全局细胞代谢的重要因素。在 arrestin 家族成员中，只有α-arrestins 具有 PY 基序，允许与 Rsp5/NEDD4 泛素连接酶的 WW 结构域进行典型结合，随后对膜蛋白进行泛素化，导致它们被液泡/溶酶体降解。α-arrestins 对不同刺激的选择性底物靶向、功能和调节的分子机制仍不完全清楚。最近已经在动物模型中对α-arrestins 的几种功能进行了描述，包括氧化还原稳态调节、先天免疫反应调节和肿瘤抑制。然而，α-arrestin 的调节和底物相互作用的分子机制主要基于酵母模型的观察结果。尽管如此，α-arrestins 与多种健康障碍有关，如糖尿病、心血管疾病、神经退行性疾病和肿瘤进展，使其成为潜在的治疗靶点之一。
