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 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.
Jinyu Li Franziska Flick Patricia Verheugd Paolo Carloni Bernhard Liischer Giulia Rossetti
Computational Biomedicine,Institute for Advanced Simulation IAS-5 and Institute ot Neuroscience and Institute of Biochemistry and Molecular Biology,RWTH Aachen University,52057,Aachen,Germany Computational Biomedicine,Institute for Advanced Simulation IAS-5 and Institute ot Neuroscience and Computational Biomedicine,Institute for Advanced Simulation IAS-5 and Institute ot Neuroscience and
国内会议
大连
英文
452-470
2016-09-24（万方平台首次上网日期，不代表论文的发表时间）