X-RAY CRYSTALLOGRAPHIC STUDIES OF NEDD4-2 UBIQUITIN PROTEIN LIGASE

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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.