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The von Hippel-Lindau protein forms fibrillar amyloid assemblies that are mitigated by the anti-amyloid molecule Purpurin.
Kumar, Vijay; Kaushik, Vibha; Kumar, Sourav; Levkovich, Shon A; Gupta, Priya; Laor Bar-Yosef, Dana; Gazit, Ehud; Segal, Daniel.
Afiliação
  • Kumar V; Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel.
  • Kaushik V; Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel.
  • Kumar S; Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel.
  • Levkovich SA; Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel.
  • Gupta P; School of Plant Sciences and Food Security, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel.
  • Laor Bar-Yosef D; Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel.
  • Gazit E; Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel; BLAVATNIK CENTER for Drug Discovery, Tel Aviv University, Tel Aviv, 6997801, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6997801, Israe
  • Segal D; Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, 6997801, Israel; BLAVATNIK CENTER for Drug Discovery, Tel Aviv University, Tel Aviv, 6997801, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6997801, Israe
Biochem Biophys Res Commun ; 690: 149250, 2024 Jan 01.
Article em En | MEDLINE | ID: mdl-38039781
The von Hippel-Lindau protein (pVHL) is a tumor suppressor involved in oxygen regulation via dynamic nucleocytoplasmic shuttling. It plays a crucial role in cell survival by degrading hypoxia-inducible factors (HIFs). Mutations in the VHL gene cause angiogenic tumors, characterized as VHL syndrome. However, aggressive tumors involving wild-type pVHL have also been described but the underlying mechanism remains to be revealed. We have previously shown that pVHL possesses several short amyloid-forming motifs, making it aggregation-prone. In this study, using a series of biophysical assays, we demonstrated that a pVHL-derived fragment (pVHL104-140) that harbors the nuclear export motif and HIF binding site, forms amyloid-like fibrillar structures in vitro by following secondary-nucleation-based kinetics. The peptide also formed amyloids at acidic pH that mimics the tumor microenvironment. We, subsequently, validated the amyloid formation by pVHL in vitro. Using the Curli-dependent amyloid generator (C-DAG) expression system, we confirmed the amyloidogenesis of pVHL in bacterial cells. The pVHL amyloids are an attractive target for therapeutics of the VHL syndrome. Accordingly, we demonstrated in vitro that Purpurin is a potent inhibitor of pVHL fibrillation. The amyloidogenic behavior of wild-type pVHL and its inhibition provide novel insights into the molecular underpinning of the VHL syndrome and its possible treatment.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Carcinoma de Células Renais / Doença de von Hippel-Lindau / Neoplasias Renais Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Carcinoma de Células Renais / Doença de von Hippel-Lindau / Neoplasias Renais Idioma: En Ano de publicação: 2024 Tipo de documento: Article