HECT, C2 And WW Domain Containing E3 Ubiquitin Protein Ligase 1 (HECW1)

NEDL1 bound translocon-associated protein-delta and also bound and ubiquitinated mutant SOD1, but not wildtype SOD1. NEDL1 associated with mutant SOD1 and ubiquitin in Lewy body-like hyaline inclusions in ventral horn motor neurons of FALS patients and mutant Sod1 transgenic mice. Mutation analysis showed that the region between the C2 domain and the first WW domain of NEDL1 was necessary for binding to mutant SOD1, whereas the 2 WW domains bound TRAPD. In vitro translated NEDL1 showed ubiquitin-protein ligase activity in the presence of UBCH5C (UBE2D3) or UBCH7 (UBE2L3). Yeast 2-hybrid screening identified dishevelled-1 (DVL1), a key transducer in the WNT signaling pathway, as a physiologic substrate for NEDL1. Mutant SOD1 interacted with DVL1 in the presence of NEDL1 and caused DVL1 dysfunction.