Biomedical Engineering Reference
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12.3.4 GATOR Complex
The multimeric GAP activity towards Rags (GATOR) complex promotes GTP
hydrolysis of RagA/B. GATOR interacts with the Rag GTPases and consists of
eight proteins divided into two subcomplexes, referred to as GATOR1 and
GATOR2 (Fig.
12.2
) (Bar-Peled et al.
2013
). GATOR1 displays GAP activity
and contains DEPDC5, Nprl2, and Nprl3. However, it is unclear which component
in the GATOR1 complex is responsible for the GAP activity. Interestingly,
DEPDC5 and Nprl2 are frequently mutated in human cancer (Lerman and Minna
2000
; Li et al.
2004
; Seng et al.
2005
). GATOR2 consists of Mios, Sec13, Seh1l,
WDR24, and WDR59 (Bar-Peled et al.
2013
), and functions to inhibit GATOR1.
Inactivation of GATOR1 renders mTORC1 resistant to amino acid deprivation,
consequently leaving mTORC1 in a constitutively active state. In contrast, knock-
down of GATOR2 inhibits mTORC1, and epistasis analysis reveals that GATOR2
negatively regulates DEPDC5.
In parallel, yeast studies revealed similar complexes which regulate TORC1
called SEACIT and SEACAT (Fig.
12.2
) (Panchaud et al.
2013
). SEACIT (similar
to GATOR1 in mammals) contains Iml1, Npr2, and Npr3. SEACAT (similar to
GATOR2 in mammals) contains Sea4, Sec13, Seh1, Sea2, and Sea3. Similar to the
mammalian studies, the GATOR1-like complex SEACIT has GAP activity towards
Gtr1 (RagA/B orthologue) in
Saccharomyces cerevisiae
. DEPDC5 yeast homo-
logue Iml1 interacts with Gtr1, stimulating its GTPase activity at the vacuole under
amino acid starvation and thus leaving TORC1 inactive. Iml1 contains a conserved
arginine that is a critical catalytic residue of GAPs. Although this arginine does not
reside within a domain containing recognizable homology to GAPs for other small
GTPases. The yeast homologues of Nprl2 (Npr2) and Nprl3 (Npr3) have previously
been described to regulate TORC1 through genome-wide screening (Neklesa and
Davis
2009
).
Noteworthy, Npr2 and Npr3 contain a N-terminus longin domain, the structure
of which is closely related to the roadblock domains and may serve as a platform for
Rag GTPase interactions (Levine et al.
2013
). Like the roadblock domains, addi-
tional repeated domains emerged when closely analyzing the GATOR complexes.
Proteins in the GATOR2 subcomplex contain WD repeats. mLST8, a component of
mTORC1, also contains WD repeats. Also, a negative regulator of mTORC1 called
Deptor (originally called DEPDC6) contains DEP domains like DEPDC5.
Although, the GATOR complexes are a very important discovery for better under-
standing the Rag GTPases, how GATOR senses amino acids is unknown. Further-
more, the mechanistic detail of how GATOR2 regulates GATOR1 is undetermined.
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