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Insight into the Mechanism of Intramolecular Inhibition of the Catalytic Activity of Sirtuin 2 (SIRT2)

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  • Jinyu Li
  • Franziska Flick
  • Patricia Verheugd
  • Paolo Carloni
  • Bernhard Lüscher
  • Giulia Rossetti

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.

Suggested Citation

  • Jinyu Li & Franziska Flick & Patricia Verheugd & Paolo Carloni & Bernhard Lüscher & Giulia Rossetti, 2015. "Insight into the Mechanism of Intramolecular Inhibition of the Catalytic Activity of Sirtuin 2 (SIRT2)," PLOS ONE, Public Library of Science, vol. 10(9), pages 1-19, September.
  • Handle: RePEc:plo:pone00:0139095
    DOI: 10.1371/journal.pone.0139095
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    References listed on IDEAS

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    1. Shin-ichiro Imai & Christopher M. Armstrong & Matt Kaeberlein & Leonard Guarente, 2000. "Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase," Nature, Nature, vol. 403(6771), pages 795-800, February.
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