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Janus‐faced Sestrin2 controls ROS and mTOR signalling through two separate functional domains
Author(s) -
Ro SeungHyun,
Kim Hanseong,
An Sojin,
Cho UhnSoo,
Lee Jun Hee
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb67
Subject(s) - mtorc1 , pi3k/akt/mtor pathway , chemistry , mechanistic target of rapamycin , microbiology and biotechnology , reactive oxygen species , biochemistry , biology , signal transduction
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. Support or Funding Information This research was supported mainly by a Pilot and Feasibility Grant from the Michigan Diabetes Research and Training Center (NIH Grant 2P30‐DK020572 to U.‐S.C. and J.H.L.) and partially by grants from Ellison Medical Foundation (AG‐NS‐0932‐12 to J.H.L.) and NIH (1R21AG050903 to U.‐S.C. and J.H.L., 1R01DK102850 to J.H.L.)