| Annotated protein: | E3 ubiquitin-protein ligase NEDD4-like (EC 2.3.2.26) (EC 2.3.2.36) (HECT-type E3 ubiquitin transferase NED4L) (NEDD4.2) (Nedd4-2). Gene symbol: NEDD4L. Taxonomy: Mus musculus (Mouse). Uniprot ID: Q8CFI0 |
| antibody wiki: | |
| SynGO gene info: | SynGO data @ NEDD4L |
| Ontology domain: | Biological Process |
| SynGO term: | regulation of postsynaptic neurotransmitter receptor endocytosis (GO:0099149) |
| Synapse type(s): | cerebral cortex, glutamatergic |
| Annotated paper: | Zhu J, et al. "Epilepsy-associated gene Nedd4-2 mediates neuronal activity and seizure susceptibility through AMPA receptors" PLoS Genet. 2017 Feb 17;13(2):e1006634 PMID:28212375 |
| Figure(s): | Figures 5-8 |
| Annotation description: | Figure 5: Nedd4-2 (NEDDL) is a ubiquitin E3 ligase that ubiquitinates GluA1 (GRIA1) at lysine-868 and mediate its surface expression in cortical neuron cultures. Figure 6, 7, 8: three epilepsy-associated missense mutations of Nedd4-2 (S233L, E271A, and H515P) exhibited reduced ability to ubiquitinate GluA1 in vitro. This also affected GluA1 surface expression. |
| Evidence tracking, Biological System: | Cultured neurons |
| Evidence tracking, Protein Targeting: | Over-expression |
| Evidence tracking, Experiment Assay: | IP + WB/MSMS Western blot |
| Annotator(s): | Frank Koopmans (ORCID:0000-0002-4973-5732) Guus Smit (ORCID:0000-0002-2286-1587) Matthijs Verhage (ORCID:0000-0002-2514-0216) |
| Lab: | Department of Functional Genomics, Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands |
| Additional literature: | an isoform of Nedd4-2, in which a N-terminal C2 domain is missing, showed extremely low affinity in ubiquitinating GluA1 but does affect synaptic strength. "Our findings therefore indicate that both C2-containing and C2-lacking Nedd4-2s function to reduce excitatory synaptic strength although most likely via distinct mechanisms." @ PMID:31357244 Nedd4-2 mediates GluA1 ubiquitination upon chronic neuronal activity stimulation, suggesting a potential role of Nedd4-2 in homeostatic synaptic downscaling @ PMID:26250624 "We found that the impaired homeostatic synaptic downscaling in Fmr1 KO neurons is caused by loss-of-function dephosphorylation of an epilepsy-associated ubiquitin E3 ligase, neural precursor cell expressed developmentally down-regulated gene 4-2, Nedd4-2. Such dephosphorylation of Nedd4-2 is surprisingly caused by abnormally stable tumor suppressor p53 and subsequently destabilized kinase Akt. Dephosphorylated Nedd4-2 fails to elicit 14-3-3-dependent ubiquitination and down-regulation of the GluA1 subunit of AMPA receptor, and therefore impairs synaptic downscaling. Most importantly, using a pharmacological inhibitor of p53, Nedd4-2 phosphorylation, GluA1 ubiquitination and synaptic downscaling are all restored in Fmr1 KO neurons." @ PMID:29771335 |
| SynGO annotation ID: | 5264 |
| Dataset release (version): | 20231201 |
| View annotation as GO-CAM model: |  |