Von Hippel-Lindau E3 ubiquitin ligase complex (VHL complex)

The Von Hippel-Lindau (VHL) E3 ubiquitin ligase complex is a multi-subunit enzyme assembly comprising the VHL tumor suppressor protein, Elongin B, Elongin C, Cullin-2, and Ring-box 1 (RBX1) [UniProt: P40337, Q15370]. This complex, often referred to as the CRL2-VHL ligase, plays a critical role in cellular oxygen sensing by targeting the alpha subunits of Hypoxia-Inducible Factors (HIF-1α and HIF-2α) for proteasomal degradation under normoxic conditions [PMID: 11130073]. When oxygen levels are sufficient, HIF-α is hydroxylated, allowing the VHL protein to recognize and bind it, subsequently leading to its ubiquitination by the Cullin-2/RBX1 catalytic core. Mutations in the VHL gene lead to VHL syndrome, characterized by the development of highly vascular tumors such as clear cell renal cell carcinoma (ccRCC) and hemangioblastomas due to constitutive HIF stabilization [PMID: 15187186]. In pharmacology, the VHL complex has gained significant prominence as a key E3 ligase recruited by Proteolysis Targeting Chimeras (PROTACs) to facilitate the targeted degradation of diverse disease-linked proteins [PMID: 26077083]. Small molecule VHL inhibitors are also being investigated for their potential to stabilize HIF in the treatment of anemia and ischemic diseases [PMID: 27748918].

Other names

CRL2-VHLVCB-Cul2 complexVHL-Elongin B-Elongin C complexVHL-CUL2-RBX1 complexCullin-RING ligase 2-VHL

Recruitment of E3 ligase for targeted protein degradation (PROTAC mechanism); Inhibition of VHL-HIF interaction to stabilize HIF transcription factors.