| Description | 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 homologues are found in organisms ranging from mammals to Drosophila and Caenorhabditis. 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 characterised 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, haemangioblastomas 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 stabilise microtubules and foster the maintenance of primary cilia. 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 [ , , , , , , , , , , , , , , , , , , , ].Von Hippel-Lindau disease tumour suppressor (VHL) has two domains: a roughly 100-residue N-terminal domain rich in β-sheet (beta domain) and a smaller α-helical domain (alpha domain), held together by two linkers and a polar interface. A large portion of the alpha domain surface, and a small portion of the beta domain interact with ElonginC. About half of the tumorigenic mutations map to the alpha domain and its residues that contact ElonginC. The remaining mutations map to the beta domain and, significantly, to a beta domain surface patch uninvolved in ElonginC binding. This suggests that two intact macromolecular binding sites may be required for the tumor suppressor effects of VHL [ ].This entry represents the alpha domain superfamily of VHL. | Name | von Hippel-Lindau disease tumour suppressor, alpha domain superfamily |
| Short Name | VHL_alpha_dom_sf | Type | Homologous_superfamily |
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