Abstract:
: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 α-Synuclein (α-Syn). These advances provided unique opportunities to elucidate the role of ubiquitination and Ub chain length in regulating α-Syn stability, aggregation, phosphorylation, and clearance. In addition, we investigated the cross-talk between phosphorylation and ubiquitination, the two most common α-Syn pathological modifications identified within Lewy bodies and Parkinson disease. Our results suggest that α-Syn functions under complex regulatory mechanisms involving cross-talk among different posttranslational modifications.
journal_name
Proc Natl Acad Sci U S Aauthors
Haj-Yahya M,Fauvet B,Herman-Bachinsky Y,Hejjaoui M,Bavikar SN,Karthikeyan SV,Ciechanover A,Lashuel HA,Brik Adoi
10.1073/pnas.1315654110subject
Has Abstractpub_date
2013-10-29 00:00:00pages
17726-31issue
44eissn
0027-8424issn
1091-6490pii
1315654110journal_volume
110pub_type
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