Role of PDZK1 in lipid metabolism and atherosclerosis.

描述(申请人提供)：接头、锚定和支架蛋白在信号转导中起重要作用。在许多情况下，信号蛋白之间的相互作用是由与特定蛋白质结构域结合的小氨基酸序列介导的，如src同源(SH)、pTyr结合(PTB)或PDZ结构域。这些相互作用负责决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，我们将其命名为PDZK1。PDZK1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，包括cMOAT(MRP2)，与多药耐药相关的管状多特异性有机阴离子转运体，囊性纤维化跨膜电导调节因子CFTR，氯通道ClC-3B，11型Na/PI共转运体，Na-H交换器NHE3，氯-阴离子交换器CFEX和高密度脂蛋白(HDL)清除剂受体SR-BI。这些新发现将PDZK1定义为膜相关蛋白组织的主要参与者，包括细胞表面受体和离子转运体。因此，PDZK1可能在脂代谢和心血管疾病、离子通道组织和多药耐药等多种生物学过程中发挥重要作用。 我们产生了一只PDZK1基因敲除小鼠，其特征是血浆胆固醇水平上升，肝脏SR-BI表达显著减少，导致“胆固醇反向运输”受损。PDZK1加入了ARM(常染色体隐性遗传性高胆固醇血症缺陷基因的产物)的行列，加入了一个可能正在增长的细胞质适配器蛋白家族，这些蛋白控制着细胞表面受体的组织特异性活动。 这项建议的目标是：1)确定PDZK1功能基因是否对动脉粥样硬化的发展具有保护作用；2)研究PDZK1与SR-BI在肝脏中相互作用的性质，并了解PDZK1在优化胆固醇反向运输中所起的作用；3)确定PDZK1在类固醇生成器官中SR-BI的组织中发挥作用的可能分子。

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.