Von Hippel-Lindau E3 ubiquitin ligase complex (VHL)

The Von Hippel-Lindau (VHL) E3 ubiquitin ligase complex is a multi-subunit enzyme assembly that plays a critical role in cellular oxygen sensing and protein homeostasis (UniProt P40337). The complex typically consists of the VHL protein (pVHL), which serves as the substrate recognition component, along with Elongin B, Elongin C, Cullin-2, and RBX1 (PMID: 11034212). Its primary biological function is the polyubiquitination of Hypoxia-Inducible Factors (HIF-1α and HIF-2α) under normoxic conditions, leading to their degradation by the 26S proteasome. In the absence of functional VHL, such as in Von Hippel-Lindau disease or clear cell renal cell carcinoma, HIF subunits accumulate and drive the transcription of genes involved in angiogenesis, erythropoiesis, and glucose metabolism (PMID: 12110844). Beyond its natural role, the VHL complex has become a prominent tool in drug discovery as a recruitment module for Proteolysis-Targeting Chimeras (PROTACs). Small-molecule VHL ligands, such as VH032, are used to tether the E3 ligase to specific pathogenic proteins, facilitating their selective degradation (PMID: 31110304). This approach allows for the targeting of proteins previously considered "undruggable" by traditional occupancy-based inhibitors.

Other names

VCB complexCRL2-VHL complexpVHL-elongin B-elongin C complexVon Hippel-Lindau tumor suppressor complex

Targeted protein degradation via PROTAC-mediated recruitment of the E3 ligase complex to a target protein, leading to polyubiquitination and proteasomal degradation (PMID: 26047124).