Reactome | SESN1,2 binds L-leucine and dissociates from GATOR2

SESN1,2 binds L-leucine and dissociates from GATOR2

Stable Identifier

R-HSA-9639287

Type

Reaction [uncertain]

Species

Homo sapiens

Compartment

lysosomal membrane

ReviewStatus

5/5

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SESN1,2 binds L-leucine and dissociates from GATOR2

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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