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

• 作 者: JinyuLi[1]FranziskaFlick[2]PatriciaVerheugd[2]PaoloCarloni[3]BernhardLiischer[2]GiuliaRossetti[4]
• 机 构: Computational Biomedicine,Institute for Advanced Simulation IAS-5 and Institute ot Neuroscience and
• 出 处: 第八届国际分子模拟与信息技术应用学术会议
• 发表日期: 2016年期

　　Sirtuin 2(SIRT2)is a NAD+-dependent deacetylase that has been associated with neurode-generation 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.