文章基本信息

标题：Synthetic polyubiquitinated α-Synuclein reveals important insights into the roles of the ubiquitin chain in regulating its pathophysiology
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作者：Mahmood Haj-Yahya ; Bruno Fauvet ; Yifat Herman-Bachinsky 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2013
卷号：110
期号：44
页码：17726-17731
DOI：10.1073/pnas.1315654110
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Ubiquitination regulates, via different modes of modifications, a variety of biological processes, and aberrations in the process have been implicated in the pathogenesis of several neurodegenerative diseases. However, our ability to dissect the pathophysiological relevance of the ubiquitination code has been hampered due to the lack of methods that allow site-specific introduction of ubiquitin (Ub) chains to a specific substrate. Here, we describe chemical and semisynthetic strategies for site-specific incorporation of K48-linked di- or tetra-Ub chains onto the side chain of Lys12 of -Synuclein (-Syn). These advances provided unique opportunities to elucidate the role of ubiquitination and Ub chain length in regulating -Syn stability, aggregation, phosphorylation, and clearance. In addition, we investigated the cross-talk between phosphorylation and ubiquitination, the two most common -Syn pathological modifications identified within Lewy bodies and Parkinson disease. Our results suggest that -Syn functions under complex regulatory mechanisms involving cross-talk among different posttranslational modifications.
关键词：chemical protein synthesis ; proteasome ; amyloid ; post-translational modifications ; fibrils