{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T21:42:23Z","timestamp":1791409343747,"version":"4.3.3"},"reference-count":34,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2009,3,19]],"date-time":"2009-03-19T00:00:00Z","timestamp":1237420800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Proteins"],"published-print":{"date-parts":[[2009,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mutations in the <jats:italic>VHL<\/jats:italic> gene lead to von Hippel\u2010Lindau (VHL) disease, a clinically heterogeneous cancer syndrome. Here, we use software and database tools to understand and predict the phenotypes associated with missense mutations in the <jats:italic>VHL<\/jats:italic> gene product, pVHL. The protein product pVHL is known to interact with elongin B, elongin C, and the HIF substrate. By analyzing known and predicted interaction sites and predictions of thermodynamic stability change upon mutation, we generate new hypotheses regarding the molecular etiology of renal cell carcinoma (RCC) and pheochromocytoma (PCC) in VHL disease. We find that the molecular causes of RCC and PCC appear to be decoupled. RCC may arise through two distinct mechanisms: disruption of HIF interactions or binding at the elongin B interface. PCC is triggered by mutations which disrupt interactions at the elongin C binding site. These findings have important implications for VHL disease and for nonfamilial RCC, because most cases of clear cell RCC are linked with <jats:italic>VHL<\/jats:italic> inactivation. Additionally, predicting effects of genetic variation will be critical as genetic sequencing accelerates; the analytical strategy presented here may elucidate other systems as further data on genetic variation become available. Proteins 2009. \u00a9 2009 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/prot.22419","type":"journal-article","created":{"date-parts":[[2009,3,19]],"date-time":"2009-03-19T19:57:43Z","timestamp":1237492663000},"page":"84-96","source":"Crossref","is-referenced-by-count":50,"title":["Structural bioinformatics mutation analysis reveals genotype\u2013phenotype correlations in von Hippel\u2010Lindau disease and suggests molecular mechanisms of tumorigenesis"],"prefix":"10.1002","volume":"77","author":[{"given":"Julia R.","family":"Forman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine L.","family":"Worth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. Richard J.","family":"Bickerton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tim G.","family":"Eisen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom L.","family":"Blundell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,4,30]]},"reference":[{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc885"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7660122"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.22.12436"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.284.5414.657"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7660130"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.14.1822"},{"key":"e_1_2_7_8_2","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1128\/MCB.18.2.732","article-title":"Regulation of the hypoxia\u2010inducible mRNAs by the von Hippel\u2010Lindau tumor suppressor protein requires binding to complexes containing elongins B\/C and Cul2","volume":"18","author":"Lonergan KM","year":"1998","journal-title":"Mol Cell Biol"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.6.2156"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.284.5413.455"},{"key":"e_1_2_7_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature00767"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1073440"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.74.082803.133142"},{"key":"e_1_2_7_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/20459"},{"key":"e_1_2_7_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2007.10.001"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2007.00827.x"},{"key":"e_1_2_7_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20385"},{"key":"e_1_2_7_18_2","doi-asserted-by":"publisher","DOI":"10.1142\/S0219720007003120"},{"key":"e_1_2_7_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2004.08.022"},{"key":"e_1_2_7_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/10.1.7"},{"key":"e_1_2_7_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btm073"},{"key":"e_1_2_7_22_2","unstructured":"WorthCL BurkeDF BlundellTL.Estimating the effects of single nucleotide polymorphisms on protein structure: how good are we at identifying likely disease associated mutations? 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