Homologous to E6AP carboxyl terminus E3 ubiquitin ligase (HECT E3 ligase) (HECT E3 ligase)

Homologous to E6AP carboxyl terminus (HECT) E3 ubiquitin ligases are a family of enzymes that play a pivotal role in the ubiquitin-proteasome system by catalyzing the final step of ubiquitin transfer to substrate proteins. Unlike RING-type ligases, HECT ligases are unique in that they form a covalent thioester intermediate with ubiquitin via a conserved cysteine residue within their C-terminal HECT domain [Source: PubMed: 21670212]. The human genome encodes 28 HECT ligases, which are subdivided into the NEDD4-like, HERC, and "other" subfamilies based on their N-terminal architecture [Source: UniProt: Family HECT]. These enzymes regulate critical cellular functions, including protein trafficking, DNA repair, and signal transduction pathways such as TGF-beta and Wnt signaling. Malfunction or expression changes in HECT ligases are linked to a variety of pathologies, including cancers (where they can act as either oncoproteins or tumor suppressors), neurodegenerative disorders like Angelman syndrome, and viral infections [Source: PubMed: 30335751]. Because of their direct catalytic role, HECT ligases are attractive therapeutic targets for small-molecule inhibition or modulation, with compounds like Heclin and arsenic trioxide demonstrating the potential to alter disease progression by restoring protein homeostasis [Source: PubMed: 22493230, PubMed: 32814834].

Other names

HECT domain-containing E3 ubiquitin protein ligaseHECT-type E3 ligaseE3 ubiquitin-protein ligase HECT-typeHECT family E3 ligase

Inhibition of the catalytic HECT domain to prevent the formation of the E3-ubiquitin thioester intermediate, thereby blocking substrate ubiquitination and subsequent degradation or signaling.