VHL Mutations Linked to Type 2C von Hippel-Lindau Disease Cause Extensive Structural Perturbations in pVHL
| Autor: | Edward J. P. Cartwright, Stefan M.V. Freund, Katja Knauth, Alexander Buchberger, Mark Bycroft |
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| Rok vydání: | 2009 |
| Předmět: |
von Hippel-Lindau Disease
endocrine system diseases Protein Conformation Protein subunit Cell Mutant Adrenal Gland Neoplasms Pheochromocytoma Biology urologic and male genital diseases Biochemistry Cell Line law.invention Pathogenesis law medicine Animals Humans Von Hippel–Lindau disease Molecular Biology Genetics Cell Biology Hypoxia-Inducible Factor 1 alpha Subunit medicine.disease Recombinant Proteins female genital diseases and pregnancy complications Cell biology medicine.anatomical_structure Von Hippel-Lindau Tumor Suppressor Protein Multiprotein Complexes Ubiquitin ligase complex Protein Structure and Folding Mutation Suppressor Protein Binding |
| Zdroj: | Journal of Biological Chemistry. 284:10514-10522 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m809056200 |
| Popis: | pVHL (von Hippel-Lindau tumor suppressor protein) is the substrate recognition subunit of the CBCVHL ubiquitin ligase complex promoting the degradation of hypoxia-inducible factor subunits, HIF-1/2α. 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-1/2α 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 CBCVHL 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-1/2α-related and -unrelated pVHL functions in the pathogenesis of pheochromocytomas. |
| Databáze: | OpenAIRE |
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