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

Area of Science:

• Biochemistry
• Molecular Biology
• Cellular Metabolism

Background:

• Sestrins are stress-inducible proteins regulating metabolism.
• They possess dual functions: reducing reactive oxygen species (ROS) and inhibiting the mechanistic target of rapamycin complex 1 (mTORC1).
• The molecular basis for these dual functions remained unclear.

Purpose of the Study:

• To elucidate the molecular mechanism behind Sestrins' dual functions.
• To determine the crystal structure of human Sestrin2 (hSesn2).
• To understand how Sestrins regulate ROS and mTORC1 signaling.

Main Methods:

• X-ray crystallography to determine the structure of human Sestrin2.
• Biochemical assays to analyze the functions of Sestrin domains.
• Structural analysis to identify functional motifs and interactions.

Main Results:

• The crystal structure reveals hSesn2 is twofold pseudo-symmetric with two distinct globular subdomains.
• The N-terminal domain (Sesn-A) contains an oxidoreductase motif that reduces alkylhydroperoxide radicals.
• The C-terminal domain (Sesn-C) is modified to interact with GATOR2, inhibiting mTORC1.

Conclusions:

• Sestrins achieve their dual role through structurally distinct N-terminal and C-terminal domains.
• This dual action of reducing ROS and inhibiting mTORC1 activation is key to attenuating aging and diabetes.
• The findings provide a molecular explanation for Sestrin's role in metabolic regulation and age-related diseases.