Neural precursor cell expressed developmentally down-regulated protein 4 (NEDD4)

Neural precursor cell expressed developmentally down-regulated protein 4 (NEDD4), commonly abbreviated as NEDD4, is a HECT-type E3 ubiquitin ligase and the founding member of the NEDD4 family[1][4]. NEDD4 catalyzes the ubiquitination of substrate proteins, tagging them for degradation or altering their activity and subcellular location. Structurally, NEDD4 contains an N-terminal C2 domain (involved in membrane association), several central WW domains (for protein-protein interactions, especially with PY motifs), and a C-terminal HECT domain (the catalytic domain responsible for ubiquitin transfer)[3][4]. NEDD4's biological roles include regulation of protein degradation, DNA damage response, cell cycle progression, cell proliferation, and apoptosis[1][3][4]. NEDD4 has been implicated in various diseases, including cancer (notably via ubiquitination and degradation of PTEN, regulating the PI3K/AKT pathway), neurodegenerative disorders, and viral infection. Recent research highlights NEDD4 as a potential therapeutic target, but as of 2024, no NEDD4-targeted drugs are in clinical use[2][3]. The enzyme’s broad involvement in cellular homeostasis presents challenges for drug development due to possible toxicity and safety concerns.

Other names

E3 ubiquitin-protein ligase NEDD4NEDD4-1KIAA0093RPF1PIG53Cell proliferation-inducing gene 53 proteinHECT-type E3 ubiquitin transferase NEDD4Neural precursor cell expressed, developmentally down-regulated 4Receptor-potentiating factor 1

Inhibition of enzyme activity by small molecule ligands targeting the HECT catalytic domain (preclinical compounds)[2].