Journal Article

FZJ-2016-00242

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Insight into the Mechanism of Intramolecular Inhibition of the Catalytic Activity of Sirtuin 2 (SIRT2)

Li, J. ; Flick, F. ; Verheugd, P. ; Carloni, P. ; Lüscher, B. ; Rossetti, G. (Corresponding author)FZJ*

2015
PLoS Lawrence, Kan.

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Please use a persistent id in citations: http://hdl.handle.net/2128/9664  doi:10.1371/journal.pone.0139095

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.

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Contributing Institute(s):

1. Computational Biomedicine (IAS-5)
2. Jülich Supercomputing Center (JSC)
3. Computational Biomedicine (INM-9)

Research Program(s):

1. 511 - Computational Science and Mathematical Methods (POF3-511) (POF3-511)
2. 571 - Connectivity and Activity (POF3-571) (POF3-571)

Appears in the scientific report 2015

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Database coverage:
; ; ; ; BIOSIS Previews ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection ; Zoological Record

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