Role of PDZK1 in lipid metabolism and atherosclerosis

PDZK1在脂质代谢和动脉粥样硬化中的作用

• 批准号: 8403749
• 负责人: Olivier N. Kocher
• 金额: $ 41.41万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403749
• 关键词: Adaptor Signaling Protein; Adhesions; Adrenal Cortex; Affect; Amino Acid Sequence; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Binding; Biochemical; Biological Process; Cancer Biology; Cardiovascular Diseases; Carrier Proteins; Cell Surface Receptors; Cell membrane; Cholesterol; Complex; Coronary heart disease; Cytoplasm; Data; Dependence; Development; Dimerization; Evaluation; Family; Genes; Goals; Hepatic; Hepatocyte; High Density Lipoproteins; In Vitro; Individual; Ion Channel; Knockout Mice; Knowledge; Laboratories; Lead; Link; Lipoproteins; Liver; Location; Mediating; Membrane Protein Traffic; Membrane Proteins; Metabolism; Methods; Molecular; Multi-Drug Resistance; Mus; Mutate; Myocardial Infarction; Names; Organ; Ovary; PDZ protein; Phosphotyrosine; Physiological; Plasma; Play; Process; Proteins; Qualifying; Role; SR-BI receptor; Scaffolding Protein; Signal Transduction; Signaling Protein; Site; Small Intestines; Structure; Techniques; Tertiary Protein Structure; Testing; Testis; Tissues; Transgenes; Transgenic Mice; Validation; X-Ray Crystallography; atheroprotective; design; high density lipoprotein receptor; hypercholesterolemia; in vivo; interest; lipid metabolism; mouse model; novel; overexpression; prevent; protein expression; receptor; research study; reverse cholesterol transport; scaffold; scavenger receptor; screening; small molecule; therapeutic target; therapy development; three dimensional structure; uptake

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 protein domains, such as src homology (SH), pTyr-binding (PTB) or PDZ domains. These interactions are responsible for determining location, function and activity of receptor and transporter proteins among others. A few years ago, we isolated a novel protein that we named PDZK1. PDZK1 contains four PDZ protein-interaction domains and interacts with the carboxy-terminal portion of a number of membrane associated proteins including the high density lipoprotein (HDL) scavenger receptor SR-BI and several ion channels, one of them involved in multidrug resistance. 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 ARH (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. More recently, we have determined, using a transgenic mouse model in which truncated forms of PDZK1 were overexpressed in the liver of PDZK1 KO mice, that all four PDZ domains of PDZK1 are necessary for normal SR-BI expression, localization and function, although the precise role of individual domains, PDZ2 and PDZ4 in particular, remains unknown. We have determined that SR-BI is able to interact with another site within PDZK1, in addition to the known interaction with PDZ1. In addition, we have solved the crystal structure of the first domain of PDZK1 and its interaction with SR-BI. We have also determined that PDZK1 is atheroprotective, suggesting that PDZK1 may be an attractive target for therapies in cardiovascular diseases. Our objectives are now to study the molecular organization of the PDZK1/SR-BI protein cluster. We will define the functions of the second and fourth PDZ domains (PDZ2 and PDZ4) of PDZK1 and identify their binding partners, define the complete structure of PDZK1 by X-ray crystallography to obtain a three dimensional structure of the molecule and understand how PDZK1 interacts with its binding partners. We will correlate the results obtained in vitro using a transgenic mouse model, where altered (mutated/truncated) PDZK1 transgenes will be expressed in the liver of PDZK1 KO mice. Such studies may provide the necessary background for the development of new therapies promoting reverse cholesterol transport to prevent the formation of atherosclerotic lesions and myocardial infarction.

接头蛋白、锚定蛋白和支架蛋白在信号转导中起着重要的作用。在许多