This title appears in the Scientific Report :
2015
Please use the identifier:
http://dx.doi.org/10.1371/journal.pone.0139095 in citations.
Please use the identifier: http://hdl.handle.net/2128/9664 in citations.
Insight into the Mechanism of Intramolecular Inhibition of the Catalytic Activity of Sirtuin 2 (SIRT2)
Insight into the Mechanism of Intramolecular Inhibition of the Catalytic Activity of Sirtuin 2 (SIRT2)
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 infor...
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Personal Name(s): | Li, Jinyu |
---|---|
Flick, Franziska / Verheugd, Patricia / Carloni, Paolo / Lüscher, Bernhard / Rossetti, Giulia (Corresponding author) | |
Contributing Institute: |
Computational Biomedicine; INM-9 Jülich Supercomputing Center; JSC Computational Biomedicine; IAS-5 |
Published in: | PLoS one, 10 (2015) 9, S. e0139095 - |
Imprint: |
Lawrence, Kan.
PLoS
2015
|
DOI: |
10.1371/journal.pone.0139095 |
PubMed ID: |
26407304 |
Document Type: |
Journal Article |
Research Program: |
Connectivity and Activity Computational Science and Mathematical Methods |
Link: |
OpenAccess OpenAccess |
Publikationsportal JuSER |
Please use the identifier: http://hdl.handle.net/2128/9664 in citations.
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. |