E3 ubiquitin-protein ligase NEDD4, also known as neural precursor cell expressed developmentally down-regulated protein 4 (whence "NEDD4") is an enzyme that is, in humans, encoded by the NEDD4 gene. NEDD4 is an E3 ubiquitin ligase enzyme, that targets proteins for ubiquitination. NEDD4 is, in eukaryotes, a highly conserved gene, and the founding member of the NEDD4 family of E3 HECT ubiquitin ligases, which in humans consists of 9 members: NEDD4 (the core topic of this article) NEDD4-2 (or NEDD4L) ITCH SMURF1 SMURF2 WWP1 WWP2 NEDL1 (HECW1) NEDDL2 (HECW2)]. NEDD4 regulates a large number of membrane proteins, such as ion channels and membrane receptors, via ubiquitination and endocytosis; its eponymous protein is widely expressed, and a large number of proteins have been predicted or demonstrated to bind in vitro. In vivo, it is involved in the regulation of a diverse range of processes, including insulin-like growth factor signalling, neuronal architecture, and viral budding. NEDD4 also is an essential protein in animals, both for development and for survival. Structure The NEDD4 protein has a modular structure that is shared among the NEDD4 family, consisting of an amino-terminal C2 calcium-dependent phospholipid binding domain, 3-4 WW protein-protein interaction domains, and a carboxyl-terminal catalytic HECT ubiquitin ligase domain. The C2 domain targets proteins to the phospholipid membrane, and can also be involved in targeting substrates. The WW domains interact with proline rich PPxY motifs in target proteins to mediate interactions with substrates and adaptors. The catalytic HECT domain forms a thioester bond with activated ubiquitin transferred from an E2 ubiquitin conjugating enzyme, before transferring ubiquitin directly to a specific substrate. Expression The human NEDD4 gene is located on chromosome 15q21.3, and consists of 30 exons that transcribe five protein variants of NEDD4, all of which vary in the C2 domain but share 100% identity from the first WW domain through to the end of the protein. The mouse Nedd4 gene is located on chromosome 9. NEDD4 is a 120kDa protein that is expressed in most tissues, including brain, heart, lung, kidney, and skeletal muscle. The NEDD4 protein localizes to the cytoplasm, mainly in the perinuclear region and cytoplasmic periphery. Function In vitro, NEDD4 has been shown to bind and ubiquitinate a number of ion channels and membrane transporters resulting in their subsequent endocytosis and degradation by the proteasome, including the epithelial sodium channel (ENaC), voltage-gated calcium and voltage-gated sodium channels. NEDD4 mediates ubiquitination and subsequent