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| Hauptseite > Workflowsammlungen > Öffentliche Einträge > Insight into the Mechanism of Intramolecular Inhibition of the Catalytic Activity of Sirtuin 2 (SIRT2) > print |
| Hauptseite > Workflowsammlungen > Öffentliche Einträge > Insight into the Mechanism of Intramolecular Inhibition of the Catalytic Activity of Sirtuin 2 (SIRT2) > print |
| 001 | 280468 | ||
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| 100 | 1 | _ | |a Li, Jinyu |0 P:(DE-Juel1)166112 |b 0 |
| 245 | _ | _ | |a Insight into the Mechanism of Intramolecular Inhibition of the Catalytic Activity of Sirtuin 2 (SIRT2) |
| 260 | _ | _ | |a Lawrence, Kan. |c 2015 |b PLoS |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1452513731_911 |2 PUB:(DE-HGF) |
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| 520 | _ | _ | |a 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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| 700 | 1 | _ | |a Flick, Franziska |0 P:(DE-HGF)0 |b 1 |
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| 700 | 1 | _ | |a Rossetti, Giulia |0 P:(DE-Juel1)145921 |b 5 |e Corresponding author |
| 773 | _ | _ | |a 10.1371/journal.pone.0139095 |g Vol. 10, no. 9, p. e0139095 - |0 PERI:(DE-600)2267670-3 |n 9 |p e0139095 - |t PLoS one |v 10 |y 2015 |x 1932-6203 |
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