title: Specific inhibition of hamster prion protein translocation by the dodecadepsipeptide valinomycin.
abstract: 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.
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Republic of Korea.
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Republic of Korea.
authors.forename: Ilho
authors.initials: I
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Joong-Yeol
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Republic of Korea; Department of Anatomy and Cell Biology, University of Ulsan College of Medicine, Seoul, Republic of Korea; Cell Dysfunction Research Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address: swkang@amc.seoul.kr.
authors.forename: Sang-Wook
authors.initials: SW
authors.lastname: Kang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D015536:Down-Regulation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D011328:Prions / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055550:Protein Stability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D013379:Substrate Specificity; D014634:Valinomycin / Q000494:pharmacology*
chemical_list: D011328:Prions; D014634:Valinomycin
keywords: Prion protein; Signal sequence; Translocation; Valinomycin; pQC pathway