Kocher Olivier, Pal Rinku, Roberts Mark, Cirovic Christine, Gilchrist Annalyn
Department of Pathology, Beth Israel-Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.
Mol Cell Biol. 2003 Feb;23(4):1175-80. doi: 10.1128/MCB.23.4.1175-1180.2003.
Proteins containing PDZ domains are involved in a large number of biological functions, including protein scaffolding, organization of ion channels, and signal transduction. We recently identified a novel PDZ domain-containing protein, PDZK1, that is selectively expressed in normal tissues, where it is associated and colocalized with MAP17, a small 17-kDa membrane-associated protein; cMOAT, an organic anion transporter implicated in multidrug resistance; and the type IIa Na/Pi cotransporter. The protein cluster formed by PDZK1, MAP17, and cMOAT is upregulated in a significant number of human carcinomas originating in the colon, breast, lung, and kidney. In order to better define the function of PDZK1 in the protein cluster and its potential role in the organization of ion channels, we generated a PDZK1 knockout mouse. While PDZK1-deficient mice developed normally, did not display any gross phenotypic abnormalities, and were fecund, lack of PDZK1 resulted in modulation of expression of selective ion channels in the kidney, as well as increased serum cholesterol levels. However, no significant redistribution of proteins known to interact with PDZK1, such as MAP17, cMOAT, and the type IIa Na/Pi cotransporter, was observed. The absence of a more significant phenotype in PDZK1-deficient mice may be due to functional compensation by other PDZ domain-containing proteins, which could be instrumental in determining the location of interacting proteins such as ion channels and other membrane-associated proteins in defined areas of the plasma membrane.
含有PDZ结构域的蛋白质参与大量生物学功能，包括蛋白质支架作用、离子通道的组织以及信号转导。我们最近鉴定出一种新型的含PDZ结构域的蛋白质——PDZK1，它在正常组织中选择性表达，在这些组织中它与MAP17（一种17 kDa的小膜相关蛋白）、cMOAT（一种与多药耐药相关的有机阴离子转运体）以及IIa型钠/磷酸共转运体相关并共定位。由PDZK1、MAP17和cMOAT形成的蛋白质簇在大量源自结肠、乳腺、肺和肾的人类癌组织中上调。为了更好地界定PDZK1在该蛋白质簇中的功能及其在离子通道组织中的潜在作用，我们培育了一种PDZK1基因敲除小鼠。虽然PDZK1缺陷小鼠发育正常，未表现出任何明显的表型异常，并且具有繁殖能力，但缺乏PDZK1导致肾脏中选择性离子通道的表达受到调节，同时血清胆固醇水平升高。然而，未观察到已知与PDZK1相互作用的蛋白质（如MAP17、cMOAT和IIa型钠/磷酸共转运体）有明显的重新分布。PDZK1缺陷小鼠中未出现更显著表型可能是由于其他含PDZ结构域的蛋白质进行了功能补偿，这可能有助于确定离子通道和其他膜相关蛋白等相互作用蛋白在质膜特定区域的位置。
