HECT, C2 and WW domain-containing E3 ubiquitin protein ligase 2 (HECW2)

HECT, C2 and WW domain-containing E3 ubiquitin protein ligase 2 (HECW2) is a protein-coding enzyme of the NEDD4 family, characterized by an N-terminal C2 domain (involved in membrane targeting), two to four WW domains (for substrate recognition and localization), and a C-terminal HECT catalytic domain. HECW2 acts as a multifunctional E3 ubiquitin ligase, mediating the ubiquitination and subsequent proteasomal degradation or stabilization of various protein substrates. It plays key roles in neural crest development by regulating GDNF/Ret signaling, stabilizing angiogenic cell junctions, maintaining nuclear protein homeostasis, and stabilizing the tumor suppressor p73. Dysregulation or mutation of HECW2 is associated with a spectrum of disorders, including neurodevelopmental delay with hypotonia and seizures, epilepsy, increased susceptibility to Hirschsprung’s disease, certain forms of cardiac arrhythmia (congenital long QT syndrome), infertility, and cancer. Its functions in both neural and vascular development, as well as in cell cycle and apoptosis regulation, underscore its importance in human physiology and disease[1][2][3][4][5].

Other names

HECW2NEDL2KIAA1301NDHSALNEDD4-like E3 ubiquitin-protein ligase 2E3 ubiquitin-protein ligase HECW2HECT-type E3 ubiquitin transferase HECW2NEDD4-related E3 ubiquitin ligase NEDL2HECT, C2 and WW domain-containing protein 2

Inhibition of voltage-gated sodium channels (as in the use of mexiletine for QT interval shortening in HECW2-variant patients)[3] Modulation of disease phenotype through targeting downstream effects of HECW2 dysfunction (inferred, not direct drug action on HECW2)