Sestrins (Sesn) are stress-inducible, highly conserved proteins in animal kingdom. Human and mouse contain three Sesns (Sesn1, Sesn2, and Sesn3) and single Sesn is available in drosophila and C.elegans. Sesn maintains metabolic homeostasis and protects cells from various stresses, such as DNA damage, oxidative stress, and hypoxia. It has been evidenced that stress-induced p53 and FoxO upregulates Sesn and then activated Sesn influences on AMPK and mTOR pathway to react on cellular stress.

Function as an antioxidant modulator of peroxiredoxins has been proposed based on the sequence homology of N-terminal Sesn with a disulfide reductase, AhpD, but many of essential sestrin functions, such as activating AMPK, do not require this reductase activity. Therefore, it is still obscure what is the exact role of Sestrins despite their functional significance in cellular level.

In collaboration with Dr. Jun-Hee Lee from UM,  we recently determined the first crystal structure of hSesn2 and uncovered the molecular mechanism by which hSesn2 plays two independent biological roles (Kim et al, 2015, Nat. Comm). Now, using single particle Cryo-EM, we try to understand the mechanism of mTORC1 regulation by determining structures of key signal intermediates, GATOR1 and GATOR2.