title: Janus-faced Sestrin2 controls ROS and mTOR signalling through two separate functional domains.
abstract: Sestrins are stress-inducible metabolic regulators with two seemingly unrelated but physiologically important functions: reduction of reactive oxygen species (ROS) and inhibition of the mechanistic target of rapamycin complex 1 (mTORC1). How Sestrins fulfil this dual role has remained elusive so far. Here we report the crystal structure of human Sestrin2 (hSesn2), and show that hSesn2 is twofold pseudo-symmetric with two globular subdomains, which are structurally similar but functionally distinct from each other. While the N-terminal domain (Sesn-A) reduces alkylhydroperoxide radicals through its helix-turn-helix oxidoreductase motif, the C-terminal domain (Sesn-C) modified this motif to accommodate physical interaction with GATOR2 and subsequent inhibition of mTORC1. These findings clarify the molecular mechanism of how Sestrins can attenuate degenerative processes such as aging and diabetes by acting as a simultaneous inhibitor of ROS accumulation and mTORC1 activation.
authors.affiliation: Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Hanseong
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Sojin
authors.initials: S
authors.lastname: An
authors.affiliation: Department of Molecular &Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Ro
authors.affiliation: Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.|Infection and Immunity Unit, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200 Porto, Portugal.|IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, 4150-180 Porto, Portugal.|ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal.
authors.forename: Filipa
authors.initials: F
authors.lastname: Teixeira
authors.affiliation: Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.|Department of Fine Chemistry, Seoul National University of Science and Technology, Seoul 139-743, Korea.
authors.forename: Gyeong Jin
authors.initials: GJ
authors.lastname: Park
authors.affiliation: Department of Fine Chemistry, Seoul National University of Science and Technology, Seoul 139-743, Korea.
authors.forename: Cheal
authors.initials: C
authors.lastname: Kim
authors.affiliation: Department of Molecular &Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Chun-Seok
authors.initials: CS
authors.lastname: Cho
authors.affiliation: Department of Molecular &Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.|Department of Obsterics and Gynecology, Soonchunhyang University Seoul Hospital, Seoul 140-743, Korea.
authors.forename: Jeong-Sig
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.|Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Ursula
authors.initials: U
authors.lastname: Jakob
authors.affiliation: Department of Molecular &Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Jun Hee
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Uhn-Soo
authors.initials: US
authors.lastname: Cho
mesh_terms: D045744:Cell Line, Tumor; D002850:Chromatography, Gel; D003460:Crystallization; D004926:Escherichia coli; D057809:HEK293 Cells; D019077:Helix-Turn-Helix Motifs; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D066298:In Vitro Techniques; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes / Q000378:metabolism*; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010088:Oxidoreductases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000084622:Sestrins
chemical_list: D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D010088:Oxidoreductases; D017382:Reactive Oxygen Species; D058570:TOR Serine-Threonine Kinases; C465398:SESN2 protein, human; D000084622:Sestrins