X-RAY CRYSTAL STUD NEDD4-2 UBIQUITIN PROTEIN LIGASE & PLASMID-ENCODED R67 DHFR

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 Nedd4是一种多模块蛋白，属于泛素蛋白连接酶家族，其特征是一个氨基末端的C2结构域，然后是2-4个连续的WW结构域，以及羧基末端的Hect结构域。Nedd4被认为是降解上皮钠通道(ENaC)的靶点。ENAC在调节血压方面起着重要作用。破坏与Nedd4相互作用的ENAC突变会导致人类高血压疾病，利德尔综合征。Nedd4的WW结构域参与了ENaC的识别。泛素化和磷酸化有许多共同之处：两者都发生得很快，通常是对细胞外信号的反应，而且都很快被一大套分别称为去泛素化酶和磷酸酶的酶逆转。显然，WW结构域是普遍存在的蛋白质模块，在蛋白质-蛋白质识别中发挥着基础作用。目的：为了了解Nedd4蛋白中特定的蛋白质-蛋白质相互作用，我们提出用X射线结晶学的方法确定Nedd4片段的结构。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Nedd4, a multi-modular protein belongs to a family of ubiquitin-protein ligases that is characterized by an amino terminal C2 domain, followed by 2-4 consecutive WW domains, and the carboxyl-terminal Hect domain. Nedd4 is known to target epithelial sodium channel (ENaC) for degradation. ENaC plays a major role in regulating blood pressure. ENaC mutations that disrupt the interaction with Nedd4 cause a human hypertensive disorder, Liddle's syndrome. Nedd4 WW domains are involved in the recognition of ENaC. Ubiquitination and phosphorylation have much in common: both occur rapidly  often in response to an extracellular signal  and both are quickly reversed by a large set of enzymes termed deubiquitination enzymes and phosphatases, respectively. It is clear that WW domains are ubiquitous protein modules and play fundamental role in protein-protein recognition. Aim: To understand specific protein-protein interactions in Nedd4 protein, we propose to determine the structure of the Nedd4 fragments by application of X-ray crystallography.