Details

Autor(en) / Beteiligte

• Kim, Jiyeon
• Choi, Ilho
• Park, Joong-Yeol
• Kang, Sang-Wook

Titel

Specific inhibition of hamster prion protein translocation by the dodecadepsipeptide valinomycin

Ist Teil von

• Experimental cell research, 2013-08, Vol.319 (13), p.2049-2057

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2013

Quelle

MEDLINE

Beschreibungen/Notizen

• Regulating the entry of secretory and membrane proteins into the ER is shown to be an important physiological process, in terms of controlling quantity, localization and therefore function of target proteins. However, few small molecule modulators are available to pharmacologically regulate translocation of a specific protein. Here, we identified a small molecule that specifically inhibits pathogenic PrP biosynthesis using a highly sensitive and reproducible assay based on the fluorogenic substrate reporter PrP. This molecule specifically destabilized the signal peptide of PrP, leading to cotranslational rerouting of a significant amount of nascent PrP to proteasome-dependent degradation pathway in the cytosol. This study suggests that regulating differential translocation efficiency attributable to sequence diversity in signal peptides of disease-causing secretory and membrane proteins using cell-permeable small molecules may be a potential therapeutic approach for diseases associated with impaired protein biogenesis. •Pharmacological regulation of protein entering the ER is shown to be an important physiological process.•Regulating the entry of secretory and membrane proteins into the ER.•Valinomycin specifically destabilizes the signal peptide of PrP.•Therapeutic mislocalization may be a potential strategy for human diseases.