HERC2–UBE3A structure uncovers a domain-motif protein network potentially altered in Angelman and related syndromes

UBE3A and HERC2 are two mutually interacting HECT E3 Ubiquitin ligases whose genes are altered in 15q11.2-13.1 Duplication (Dup15q) Syndrome, Angelman Syndrome (AS) and other phenotypically-related mental retardation syndromes. Using quantitative binding assays, X-ray crystallography and sequence conservation analysis, we characterize the core interface of the HERC2-UBE3A complex, involving the RLD2 domain of HERC2 and a “DxDKDxD” sequence from a disordered region of UBE3A. The sequence determinants of the interface are conserved in numerous animals with a central nervous system. HERC2 also binds similar DxDKDxD motifs within a handful of other proteins relevant to brain development (DOCK10, PCM1, USP35, BAZ2B, ARID4A, ARIP4, RERE and MYT1). We further investigate the interaction of HERC2 with DOCK10, a RAC1- and CDC42-GEF protein that regulates dendritic spine morphogenesis in hippocampal neurons. siRNA-mediated knockdown of HERC2 affects the GEF activity of DOCK10, and mutagenesis of the HERC2-binding motif in DOCK10 disrupts both its GEF activity and its ability to drive dendritic spine formation. In developing brains, an abnormal dosage of either HERC2 or its dominant partner UBE3A may thus alter the proportions of RLD2-mediated complexes, including HERC2-DOCK10, and may thereby perturb dendritic spine morphogenesis and neurodevelopment. UBE3A and HERC2 are two interacting HECT E3 ligases altered in Angelman and related neurodevelopmental syndromes. Here the authors show UBE3A to bind HERC2 via a “DxDKDxD” motif found in nine additional HERC2-binding brain proteins, suggesting a HERC2-centered network relevant for neurodevelopment.