HECT, UBA, and WWE domain-containing E3 ubiquitin-protein ligase 1 (HUWE1)

HECT, UBA, and WWE domain-containing E3 ubiquitin-protein ligase 1 (HUWE1) is a large (~482 kDa) modular **E3 ubiquitin ligase** of the HECT family that regulates the stability and turnover of multiple cellular proteins including regulators of apoptosis (MCL-1), tumor suppressors (p53), and oncogenes (MYC, N-MYC). HUWE1 transfers ubiquitin from an E2 conjugase to specific substrate proteins, targeting them for proteasomal degradation. Its activity is tightly controlled by conformational mechanisms including dimerization, auto-inhibition, and interactions with regulatory proteins such as p14ARF. Structurally, HUWE1 contains a catalytic HECT domain, UBA and WWE protein-interaction domains, and other regions that facilitate substrate recognition and regulatory interactions. It is involved in fundamental processes such as DNA replication and repair, cell cycle progression, apoptosis, and protein quality control. HUWE1 is often overexpressed in cancer and has complex context-dependent functions that can either promote or suppress tumorigenesis. While HUWE1 is considered a promising therapeutic target, there are currently no approved drugs that directly target HUWE1[1][2][3].

Other names

HUWE1MuleARF-BP1HectH9LASU1UREB1URE-B1URE-binding protein 1KIAA0312KIAA1578HSPC272Ib772ARF-binding protein 1MRXSTlarge structure of UREB1Mcl-1 ubiquitin ligase E3upstream regulatory element-binding protein 1

For hypothetical inhibitors: Inhibition of HUWE1’s E3 ligase function prevents ubiquitination and proteasomal degradation of oncogenic or regulatory proteins[1]. - For peptide inhibitors: Stabilization of HUWE1’s auto-inhibited/dimeric state to block its activity[1]. - siRNA or genetic knockdown: Reduces HUWE1 levels and substrate degradation[2].