Department of Cell Biology, The University of Oklahoma Health Sciences Center, BRC262, 975 NE 10th Street, Oklahoma City, OK 73104, United States of America.
Cell Signal. 2020 Aug;72:109640. doi: 10.1016/j.cellsig.2020.109640. Epub 2020 Apr 17.
Naturally occurring mutations in two separate genes, PKD1 and PKD2, are responsible for the vast majority of all cases of autosomal dominant polycystic kidney disease (ADPKD), one of the most common genetic diseases affecting 1 in 1000 Americans. The hallmark of ADPKD is the development of epithelial cysts in the kidney, liver, and pancreas. PKD1 encodes a large plasma membrane protein (PKD1, PC1, or Polycystin-1) with a long extracellular domain and has been speculated to function as an atypical G protein coupled receptor. PKD2 encodes an ion channel of the Transient Receptor Potential superfamily (TRPP2, PKD2, PC2, or Polycystin-2). Despite the identification of these genes more than 20 years ago, the molecular function of their encoded proteins and the mechanism(s) by which mutations in PKD1 and PKD2 cause ADPKD remain elusive. Genetic, biochemical, and functional evidence suggests they form a multiprotein complex present in multiple locations in the cell, including the plasma membrane, endoplasmic reticulum, and the primary cilium. Over the years, numerous interacting proteins have been identified using directed and unbiased approaches, and shown to modulate function, cellular localization, and protein stability and turnover of Polycystins. Delineation of the molecular composition of the Polycystin complex can have a significant impact on understanding their cellular function in health and disease states and on the identification of more specific and effective therapeutic targets.
两个独立基因 PKD1 和 PKD2 的自然突变导致绝大多数常染色体显性遗传性多囊肾病（ADPKD），这是一种最常见的遗传疾病，影响了每 1000 个美国人中的 1 个。ADPKD 的标志是肾脏、肝脏和胰腺上皮囊肿的形成。PKD1 编码一个大型质膜蛋白（PKD1、PC1 或多囊蛋白-1），具有长的细胞外结构域，并被推测作为一种非典型 G 蛋白偶联受体发挥作用。PKD2 编码瞬时受体电位超家族的离子通道（TRPP2、PKD2、PC2 或多囊蛋白-2）。尽管这些基因在 20 多年前就被发现，但它们编码的蛋白质的分子功能以及 PKD1 和 PKD2 突变导致 ADPKD 的机制仍不清楚。遗传、生化和功能证据表明，它们形成一个多蛋白复合物，存在于细胞的多个位置，包括质膜、内质网和初级纤毛。多年来，使用定向和非定向方法已经鉴定出许多相互作用的蛋白质，并显示它们可以调节多囊蛋白的功能、细胞定位以及蛋白质稳定性和周转率。多囊蛋白复合物的分子组成的描述可以对理解它们在健康和疾病状态下的细胞功能以及鉴定更具体和有效的治疗靶点产生重大影响。
