ArticleThe Journal of biological chemistry2009
VHL mutations linked to type 2C von Hippel-Lindau disease cause extensive structural perturbations in pVHL.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 29 citations in OpenAlex.
- Rescuing the Function of Missense-Mutated Tumor SuppressorbioRxiv : the preprint server for biology · 2026Article
- Article
- Characterization of the Pheochromocytoma-Predominant Subgroup of von Hippel-Lindau Disease.Urology · 2025Article
- Article
- Mutation of the proline P81 into a serine modifies the tumour suppressor function of the von Hippel-Lindau gene in the ccRCC.British journal of cancer · 2022Article
- Article
- The von Hippel-Lindau Cullin-RING E3 ubiquitin ligase regulates APOBEC3 cytidine deaminases.Translational research : the journal of laboratory and clinical medicine · 2021Article
- Targeting the RhoGTPase/ROCK pathway for the treatment of VHL/HIF pathway-driven cancers.Small GTPases · 2020Review
- Article
- Management of Gene Variants of Unknown Significance: Analysis Method and Risk Assessment of theCurrent genomics · 2017Review
- Article
- Is NMR Fragment Screening Fine-Tuned to Assess Druggability of Protein-Protein Interactions?ACS medicinal chemistry letters · 2014Article
- The interaction of the von Hippel-Lindau tumor suppressor and heterochromatin protein 1.Archives of biochemistry and biophysics · 2012Article
- Quantitative image analysis identifies pVHL as a key regulator of microtubule dynamic instability.The Journal of cell biology · 2010Article
- The SOCS-box of HIV-1 Vif interacts with ElonginBC by induced-folding to recruit its Cul5-containing ubiquitin ligase complex.PLoS pathogens · 2010Article
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
pVHL (von Hippel-Lindau tumor suppressor protein) is the substrate recognition subunit of the CBC(VHL) ubiquitin ligase complex promoting the degradation of hypoxia-inducible factor subunits, HIF-1/2alpha. Mutational inactivation of pVHL causes the hereditary von Hippel-Lindau tumor syndrome, which predisposes affected individuals to hemangioblastomas, renal cell carcinomas, and pheochromocytomas. Whereas the development of hemangioblastomas and renal cell carcinomas has been attributed to impaired HIF-1/2alpha down-regulation by pVHL mutant proteins, the molecular defects underlying the development of pheochromocytomas are still unknown. Here, we present a detailed biochemical analysis of pVHL mutant proteins linked to type 2C (pheochromocytoma only) von Hippel-Lindau disease. Type 2C-associated mutations caused extensive structural perturbations of pVHL, as revealed by the reduced stability, increased proteolytic susceptibility, and dramatically altered NMR spectrum of recombinant, mutant pVHL-ElonginC-ElonginB complexes in vitro. In human cell lines, type 2C-linked mutations destabilized the CBC(VHL) ubiquitin ligase complex and resulted in reduced cellular pVHL levels. Together, our data reveal unexpectedly strong structural defects of type 2C-associated pVHL mutant proteins that are likely to affect both HIF-1/2alpha-related and -unrelated pVHL functions in the pathogenesis of pheochromocytomas.
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