4n7f | pdb_00004n7f
Crystal structure of 3rd WW domain of human Nedd4-1
Structural highlights
FunctionNEDD4_HUMAN E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Involved in the pathway leading to the degradation of VEGFR-2/KDFR, independently of its ubiquitin-ligase activity. Monoubiquitinates IGF1R at multiple sites, thus leading to receptor internalization and degradation in lysosomes. Ubiquitinates FGFR1, leading to receptor internalization and degradation in lysosomes. According to PubMed:18562292 the direct link between NEDD4 and PTEN regulation through polyubiquitination described in PubMed:17218260 is questionable. Involved in ubiquitination of ERBB4 intracellular domain E4ICD. Involved in the budding of many viruses. Part of a signaling complex composed of NEDD4, RAP2A and TNIK which regulates neuronal dendrite extension and arborization during development. Ubiquitinates TNK2 and regulates EGF-induced degradation of EGFR and TNF2.[1] [2] [3] [4] [5] Publication Abstract from PubMedFollowing protracted stimulation, the beta2-adrenergic receptor (beta2AR) and many other G-protein-coupled receptors (GPCRs) are ubiquitinated and downregulated. Arrestin-Related Domain-Containing Protein-3 (ARRDC3) is an alpha-arrestin that recruits the ubiquitin ligase Nedd4 to the beta2AR. ARRDC3 contains two PPXY motifs that could potentially interact with any of the four WW domains of Nedd4. Here we dissect the interaction determinants. ARRDC3 PPXY-Nedd4 WW dissociation constants vary from unmeasurable to Kd = 3 muM for the third WW domain of Nedd4 binding to the first PPXY motif of Nedd4. Structures of the uncomplexed and PPXY1-bound WW3 domain were determined at 1.1 and 1.7 Angstrom resolution. The structures revealed conformational changes upon binding and the hydrogen bonding network in exquisite detail. Tight packing of ARRDC3 Val352, part of a 310 helix at the C-terminus of PPXY1, is important for high affinity binding to WW3. Although no single WW domain is strictly essential for the binding of Nedd4 and ARRDC3 expressed in HEK293 cells, high affinity binding of full-length ARRDC3 and Nedd4 is driven by the avid interaction of both PPXY motifs with either the WW2-WW3 or WW3-WW4 combinations, with Kd values as low as 300 nM. Structural and Biochemical Basis for Ubiquitin Ligase Recruitment by Arrestin-Related Domain-Containing Protein-3 (ARRDC3).,Qi S, O'Hayre M, Gutkind JS, Hurley JH J Biol Chem. 2013 Dec 30. PMID:24379409[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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