E3ubiquitinligas

E3 ubiquitin ligases are enzymes in the ubiquitin–proteasome system that catalyze the transfer of ubiquitin to target proteins. By tagging substrates with ubiquitin, they regulate protein stability, signaling, and localization, influencing numerous cellular processes. E3 ligases confer substrate specificity in the ubiquitination cascade, working alongside ubiquitin-activating enzymes (E1) and ubiquitin-conjugating enzymes (E2).

Most ubiquitination is carried out by three broad classes of E3 ligases: RING-type, HECT-type, and RBR-type. In RING ligases, the enzyme binds both the E2–ubiquitin conjugate and the substrate, promoting direct transfer of ubiquitin. HECT ligases form a transient E3–ubiquitin thioester intermediate before transferring ubiquitin to the substrate. RBR ligases combine features of both, forming an intermediate before ubiquitin transfer. Ubiquitin chains can take various linkage types, such as K48-linked chains that typically target proteins for proteasomal degradation, and K63-linked chains that modulate signaling and trafficking without necessarily causing degradation.

E3 ligases regulate essential cellular functions including cell cycle progression, DNA repair, and immune responses. Dysregulation or mutation of E3 ligases is linked to diseases such as cancer and neurodegenerative disorders. Notable examples include MDM2, which ubiquitinates p53; VHL, which targets hypoxia-inducible factor 1α; and Parkin, a RBR ligase implicated in Parkinson’s disease. E3 ligases are also central to targeted protein degradation strategies in drug discovery, where arrangers like cereblon, VHL, MDM2, and cIAP1/2 are recruited by PROTACs to destroy disease-associated proteins.

Overall, E3 ubiquitin ligases represent a large and diverse family that controls proteostasis and cellular signaling, with significant implications for biology and therapy.