SESN1,2 binds L-leucine and dissociates from GATOR2

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Reaction [BlackBoxEvent]
Homo sapiens
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SESN2 (Sestrin2) and SESN1 (Sestrin1) each interact with the GATOR2 complex in the absence of leucine and, upon binding leucine, dissociate from the GATOR2 complex (Chantranupong et al. 2014, Parmigiani et al. 2014, Kim et al. 2015, Wolfson et al. 2016, Saxton et al. 2016). (SESN3 constitutively binds GATOR2 in the presence and absence of leucine.) When bound to GATOR2, the Sestrins appear to prevent GATOR2 from inhibiting GATOR1, a GTPase activator which negatively regulates mTORC1 activation by increasing the rate of hydrolysis of RRAGA,B:GTP to RRAGA,B:GDP. SESN1,2 complexed with GATOR2 therefore allows GATOR1 to maintain mTORC1 in the inactive state (Chantranupong et al. 2014, Parmigiani et al. 2014, Kim et al. 2015). L-leucine binds SESN1,2 and causes SESN1,2 to dissociate from GATOR2, allowing GATOR2 to inhibit GATOR1 and thereby maintain RRAGA,B in the active (GTP-bound) state (Wolfson et al. 2016, Saxton et al. 2016). GATOR1 is recruited to the lysosomal membrane by the KICSTOR complex (Wolfson et al. 2017, Peng et al. 2017).
Sestrins also appear to interact with the Rag heterodimer (Peng et al. 2014) though the interaction may be indirect (Budanov 2015).

Literature References
PubMed ID Title Journal Year
27308486 SESTRINs regulate mTORC1 via RRAGs: The riddle of GATOR

Budanov, AV

Mol Cell Oncol 2015
25819761 Sestrin2 inhibits mTORC1 through modulation of GATOR complexes

Lee, JH, Semple, IA, Ro, SH, Cho, US, Guan, KL, Park, H, Park, HW, Kim, M, Wang, W, Karin, M, Kim, JS

Sci Rep 2015
28199306 KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1

Sabatini, DM, Petri, S, Condon, KJ, Shen, K, Orozco, JM, Scaria, SM, Gu, X, Frankel, WN, Chantranupong, L, Kedir, J, Abu-Remaileh, M, Wyant, GA, Wolfson, RL

Nature 2017
26586190 Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway

Sabatini, DM, Schwartz, TU, Wang, T, Pacold, ME, Saxton, RA, Chantranupong, L, Knockenhauer, KE, Wolfson, RL

Science 2016
25263562 The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1

Sabatini, DM, Scaria, SM, Spooner, E, Saxton, RA, Gygi, SP, Bar-Peled, L, Chantranupong, L, Isasa, M, Orozco, JM, Wolfson, RL

Cell Rep 2014
28199315 SZT2 dictates GATOR control of mTORC1 signalling

Peng, M, Li, MO, Yin, N

Nature 2017
25457612 Sestrins inhibit mTORC1 kinase activation through the GATOR complex

Budanov, AV, Nourbakhsh, A, Ding, B, Guan, KL, Kim, YC, Akopiants, K, Wang, W, Karin, M, Parmigiani, A

Cell Rep 2014
25259925 Sestrins function as guanine nucleotide dissociation inhibitors for Rag GTPases to control mTORC1 signaling

Peng, M, Li, MO, Yin, N

Cell 2014
26449471 Sestrin2 is a leucine sensor for the mTORC1 pathway

Sabatini, DM, Scaria, SM, Saxton, RA, Chantranupong, L, Cantor, JR, Shen, K, Wolfson, RL

Science 2016
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