POLYCYSTIN G PROTEIN SIGNAL TRANSDUCTION

多囊蛋白 G 信号转导

• 批准号: 6655213
• 负责人: james p calvert
• 金额: $ 16.2万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6655213
• 关键词: G protein; biological signal transduction; genetically modified animals; laboratory mouse; membrane proteins; phenotype; polycystic kidney; protein protein interaction; protein structure function; receptor coupling; site directed mutagenesis

Description: (Taken directly from the application) Mutations in the PKD 1 gene cause 80-90% of the cases of polycystic kidney disease. These mutations give rise to cyst growth and enlargement, ultimately leading to the development of polycystic kidneys and to extrarenal manifestations of the disease, including Ever and pancreatic cysts, cerebral and aortic aneurysms, and heart valve defects. However, the function of the normal PKD 1 gene is not known and thus it is not understood how mutations in the PKD1 gene give rise to the disease pathogenesis associated with PKD. As such, it will be important to understand the biochemical and cellular functions of the PKD1 gene in order to gain insight into the aberrant mechanisms that occur upon initiation of the disease, and to design therapeutic interventions to treat or slow disease progression. The PKD 1 gene encodes an approximately 400 kDa protein, polycystin-1, that has been hypothesized function as a plasm membrane receptor. Sequence analysis has revealed that the C-terminal cytosolic domain of polycystin-1 has a number of conserved motifs that suggest that it functions by mediating signal transduction. This idea is supported by our new preliminary evidence that demonstrates that the C-terminal tail of polycystin-1 binds and activates heterotrimeric G-proteins; in vitro, and that it can be phosphorylated both in vitro and in vivo. If it can be confirmed that polycystin-1 directly interacts with heterotrimeric G-proteins, polycystin will be placed in the mainstream of a number of possible signal transduction pathways. Our general hypothesis is that polycystin-1 functions as a G-protein coupled receptor. This hypothesis will be tested by the following Specific Aims: Aim 1. Amino acid residues required for the in vitro binding interaction between polycystin-1 and heterotrimeric G-proteins will be determined. Aim 2. The potential for polycystin-1 to engage in heterotrimeric G-protein coupled signal transduction will be determined. Aim 3. The potential for polycystin-1 to interact with regulators of heterotrimeric G-protein coupled receptors will be determined. Aim 4. The importance of the conserved G-protein activation domain will be tested in transgenic mice.

描述：（直接从应用程序中获取）pkd1基因突变导致80-90%的多囊肾病病例。这些突变导致囊肿生长和扩大，最终导致多囊肾的发展和该病的肾外表现，包括Ever囊肿和胰腺囊肿、脑动脉瘤和主动脉瘤以及心脏瓣膜缺陷。然而，正常PKD1基因的功能尚不清楚，因此PKD1基因的突变如何引起与PKD相关的疾病发病机制尚不清楚。因此，了解PKD1基因的生化和细胞功能将是非常重要的，以便深入了解疾病发生时发生的异常机制，并设计治疗干预措施来治疗或减缓疾病进展。PKD -1基因编码一种大约400 kDa的蛋白，多囊蛋白-1，它被认为是一种质膜受体。序列分析表明，多囊蛋白-1的c端胞质结构域具有许多保守的基序，表明其通过介导信号转导起作用。这一观点得到了我们新的初步证据的支持，这些证据表明，多胱氨酸-1的c端尾部结合并激活异源三聚体g蛋白；它在体外和体内都可以被磷酸化。如果能证实多囊蛋白-1与异源三聚体g蛋白直接相互作用，多囊蛋白将被置于许多可能的信号转导途径的主流。我们的一般假设是多囊蛋白-1作为g蛋白偶联受体起作用。这一假设将通过以下具体目标进行检验：目标1。多胱氨酸-1和异三聚体g蛋白之间的体外结合相互作用所需的氨基酸残基将被确定。目标2。多囊蛋白-1参与异源三聚体g蛋白偶联信号转导的潜力将被确定。目标3。多胱氨酸-1与异源三聚体g蛋白偶联受体的调节因子相互作用的潜力将被确定。目标4。保守的g蛋白激活域的重要性将在转基因小鼠中进行测试。