von Hippel-Landau (pVHL) protein, the gene product of VHL, is a critical regulator of the ubiquitous oxygen-sensing pathway. It is conserved throughout evolution, as its homologs are found in organisms ranging from mammals to the Drosophila melanogaster, Anopheles gambiae insects and the Caenorhabditis elegans nematode. pVHL acts as the substrate recognition component of an E3 ubiquitin ligase complex. Several proteins have been identified as pVHL-binding proteins that are subject to ubiquitin-mediated proteolysis; the best characterized putative substrates are the alpha subunits of the hypoxia-inducible factor (HIF1alpha, HIF2alpha, and HIF3alpha). In addition to HIF degradation, pVHL has been implicated to be involved in HIF independent cellular processes. Germline VHL mutations cause renal cell carcinomas, hemangioblastomas and pheochromocytomas in humans. pVHL can bind to and direct the proper deposition of fibronectin and collagen IV within the extracellular matrix. It works to stabilize microtubules and foster the maintenance of primary cilium. It also has been reported to promote the stabilization and activation of p53 in a HIF-independent manner and, in neuronal cells, promote apoptosis by down-regulation of Jun-B.
Comment:For ubiquitination of the hypoxia-inducible factor (HIF) by the von Hippel-Lindau tumor suppressor (pVHL) to occur, pVHL binds to HIF only when a conserved proline in HIF is hydroxylated, a modification that is oxygen-dependent.
Structure:1LM8: Human von Hippel-Lindau tumor suppressor (pVHL) bound to 20 residue HIF-1alpha peptide; contacts at 4.0A - View structure with Cn3D