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- W2227804297 endingPage "e0139095" @default.
- W2227804297 startingPage "e0139095" @default.
- W2227804297 abstract "Sirtuin 2 (SIRT2) is a NAD+-dependent deacetylase that has been associated with neurodegeneration and cancer. SIRT2 is composed of a central catalytic domain, the structure of which has been solved, and N- and C-terminal extensions that are thought to control SIRT2 function. However structural information of these N- and C-terminal regions is missing. Here, we provide the first full-length molecular models of SIRT2 in the absence and presence of NAD+. We also predict the structural alterations associated with phosphorylation of SIRT2 at S331, a modification that inhibits catalytic activity. Bioinformatics tools and molecular dynamics simulations, complemented by in vitro deacetylation assays, provide a consistent picture based on which the C-terminal region of SIRT2 is suggested to function as an autoinhibitory region. This has the capacity to partially occlude the NAD+ binding pocket or stabilize the NAD+ in a non-productive state. Furthermore, our simulations suggest that the phosphorylation at S331 causes large conformational changes in the C-terminal region that enhance the autoinhibitory activity, consistent with our previous findings that phosphorylation of S331 by cyclin-dependent kinases inhibits SIRT2 catalytic activity. The molecular insight into the role of the C-terminal region in controlling SIRT2 function described in this study may be useful for future design of selective inhibitors targeting SIRT2 for therapeutic applications." @default.
- W2227804297 created "2016-06-24" @default.
- W2227804297 creator A5025243974 @default.
- W2227804297 creator A5026564872 @default.
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- W2227804297 creator A5041462448 @default.
- W2227804297 creator A5043471682 @default.
- W2227804297 creator A5049856377 @default.
- W2227804297 date "2015-09-25" @default.
- W2227804297 modified "2023-10-14" @default.
- W2227804297 title "Insight into the Mechanism of Intramolecular Inhibition of the Catalytic Activity of Sirtuin 2 (SIRT2)" @default.
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- W2227804297 doi "https://doi.org/10.1371/journal.pone.0139095" @default.
- W2227804297 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/4583397" @default.
- W2227804297 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26407304" @default.
- W2227804297 hasPublicationYear "2015" @default.
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