Role of PDZK1 in lipid metabolism and atherosclerosis.

描述（由申请人提供）：衔接蛋白、锚定蛋白和支架蛋白在信号转导中起重要作用。在许多情况下，信号传导蛋白之间的相互作用是由与特定蛋白结构域结合的小氨基酸序列介导的，所述特定蛋白结构域例如src同源性（SH）、pTyr结合（PTB）或PDZ结构域。这些相互作用负责确定受体和转运蛋白等的位置、功能和活性。几年前，我们分离出一种新的蛋白质，我们命名为PDZK 1。PDZK 1含有四个PDZ蛋白相互作用结构域，并与许多膜相关蛋白的羧基末端部分相互作用，所述膜相关蛋白包括与多药耐药性相关的小管多特异性有机阴离子转运蛋白cMOAT（MRP 2）、囊性纤维化跨膜传导调节因子CFTR、氯离子通道CLC-3B、IIa型Na/Pi共转运蛋白、Na-H交换剂NHE 3、氯离子交换剂CFEX和高密度脂蛋白（HDL）清除剂受体SR-BI。这些新发现将PDZK 1定义为膜相关蛋白（包括细胞表面受体和离子转运蛋白）组织的主要参与者。因此，PDZK 1可能在脂质代谢和心血管疾病、离子通道组织和多药耐药性等多种生物过程中发挥重要作用。 我们建立了一个PDZK 1基因敲除小鼠，其特征是血浆胆固醇水平升高，肝脏中SR-BI的表达显著降低，导致胆固醇逆向转运受损。“PDZK 1加入ARM（常染色体隐性高胆固醇血症中缺陷基因的产物），可能是一个不断增长的细胞质衔接蛋白家族，控制细胞表面受体的组织特异性活性。 该提议的目标是：1）确定功能性PDZK 1基因是否对动脉粥样硬化的发展具有保护作用，2）研究肝脏中PDZK 1和SR-BI之间相互作用的性质，并了解PDZK 1在优化胆固醇逆向转运中所起的作用，3）鉴定在类固醇生成器官中SR-BI的组织中起PDZK 1作用的推定分子。

DESCRIPTION (provided by applicant): Adaptor, anchoring and scaffolding proteins play an important role in signal transduction. In many situations, the interaction between signaling proteins is mediated by small amino acid sequences binding to specific proteins domains, such as src homology (SH), pTyr-binding (PTB) or PDZ domains. These interactions are responsible for determining location, function and activity of receptors and transporter proteins among others. A few years ago, we isolated a novel protein that we named PDZK1. PDZK1, contains four PDZ protein-interactions domains and interacts with the carboxy-terminal portion of a number of membrane associated proteins including cMOAT (MRP2) the canalicular multispecific organic anion transporter associated with multidrug resistance, the cystic fibrosis transmembrane conductance regulator CFTR, the chloride channel CLC-3B, the type lla Na/Pi cotransporter, the Na-H exchanger NHE3, the chloride-anion exchanger CFEX and the high density lipoprotein (HDL) scavenger receptor SR-BI. These new findings define PDZK1 as a major player in the organization of membrane associated proteins including cell surface receptors and ion transporters. As a result, PDZK1 is likely to play an important role in biological processes as diverse as lipid metabolism and cardiovascular disease, ion channel organization and multidrug resistance. We generated a PDZK1 knockout mouse which is characterized by increased plasma cholesterol levels and markedly reduced expression of SR-BI in the liver, resulting in impaired "reverse cholesterol transport." PDZK1 joins ARM (the product of the defective gene in autosomal recessive hypercholesterolemia) in what is likely to be a growing family of cytoplasmic adaptor proteins that control the tissue specific activity of cell surface receptors. The goals of this proposal are: 1) to determine if a functional PDZK1 gene is protective against the development of atherosclerosis, 2) to study the nature of the interaction between PDZK1 and SR-BI in the liver and understand the role played by PDZK1 in optimizing reverse cholesterol transport, 3) to identify the putative molecule that plays the role of PDZK1 in the organization of SR-BI in steroidogenic organs.