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

The Von Hippel-Lindau (VHL) E3 ubiquitin ligase complex is a multi-subunit Cullin-RING ligase (CRL2-VHL) that serves as a master regulator of the cellular response to hypoxia (UniProt: P40337). The complex is composed of the VHL tumor suppressor protein, which acts as the substrate recognition component, along with Elongin B, Elongin C, Cullin-2, and RBX1 (NCBI Gene: 7428). Under normoxic conditions, the VHL protein identifies and binds to prolyl-hydroxylated hypoxia-inducible factors (HIF-1α and HIF-2α), leading to their polyubiquitination and subsequent degradation by the 26S proteasome (PubMed: 11130073). Mutations in the VHL gene result in the stabilization of HIF proteins, driving the transcription of genes involved in angiogenesis and cell proliferation, which leads to Von Hippel-Lindau syndrome and clear cell renal cell carcinoma (NIH: StatPearls). In modern drug discovery, the VHL complex is a primary tool for Proteolysis Targeting Chimera (PROTAC) technology, where small-molecule VHL ligands like VH032 are used to recruit the ligase to degrade non-native pathogenic proteins (PubMed: 26074456). While direct inhibitors of the VHL-HIF interaction are a focus of research, clinical management of VHL-related diseases often involves downstream inhibitors such as belzutifan, which targets HIF-2α (FDA: Belzutifan Approval).

Other names

VCB complexCRL2-VHL complexVHL-Elongin C-Elongin B complexpVHL complexCullin-RING ligase 2-VHL

The complex functions as an E3 ubiquitin ligase that targets specific proteins, most notably hydroxylated HIF-1α and HIF-2α, for polyubiquitination and subsequent degradation by the 26S proteasome. In drug development, VHL ligands are used in PROTACs to recruit the complex to neo-substrates, inducing their degradation.