title: Insight into the Mechanism of Intramolecular Inhibition of the Catalytic Activity of Sirtuin 2 (SIRT2).
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.
authors.affiliation: Computational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich, 52425, Jülich, Germany; Institute of Biochemistry and Molecular Biology, RWTH Aachen University, 52057, Aachen, Germany.
authors.forename: Jinyu
authors.initials: J
authors.lastname: Li
authors.affiliation: Institute of Biochemistry and Molecular Biology, RWTH Aachen University, 52057, Aachen, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Flick
authors.affiliation: Institute of Biochemistry and Molecular Biology, RWTH Aachen University, 52057, Aachen, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Verheugd
authors.affiliation: Computational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich, 52425, Jülich, Germany; Computational Biophysics, German Research School for Simulation Sciences, Forschungszentrum Jülich, 52425, Jülich, Germany.
authors.forename: Paolo
authors.initials: P
authors.lastname: Carloni
authors.affiliation: Institute of Biochemistry and Molecular Biology, RWTH Aachen University, 52057, Aachen, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Lüscher
authors.affiliation: Computational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich, 52425, Jülich, Germany; Jülich Supercomputing Centre, Forschungszentrum Jülich, 52425, Jülich, Germany; Department of Oncology, Hematology and Stem Cell Transplantation, RWTH Aachen University, Aachen, Germany.
authors.forename: Giulia
authors.initials: G
authors.lastname: Rossetti
mesh_terms: D001665:Binding Sites; D002384:Catalysis; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010766:Phosphorylation; D011487:Protein Conformation; D056565:Sirtuin 2 / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D013329:Structure-Activity Relationship
chemical_list: C418743:Sirt2 protein, mouse; D056565:Sirtuin 2