Janus-faced Sestrin2 controls ROS and mTOR signalling through two separate functional domains

Authors

Hanseong Kim, University of Michigan-Ann Arbor
Sojin An, University of Michigan-Ann Arbor
Seung-Hyun Ro, University of Nebraska-LincolnFollow
Filipa Teixeira, University of Michigan-Ann Arbor
Gyeong Jin Park, University of Michigan-Ann Arbor
Cheal Kim, Seoul National University of Science and Technology
Chun-Seok Cho, University of Michigan-Ann Arbor
Jeong-Sig Kim, University of Michigan-Ann Arbor
Ursula Jakob, University of Michigan-Ann Arbor
Jun Hee Lee, University of Michigan-Ann Arbor
Uhn-Soo Cho, University of Michigan-Ann Arbor

Date of this Version

2015

Citation

NATURE COMMUNICATIONS | 6:10025

Comments

Open access

DOI: 10.1038/ncomms10025

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.