RRC ID |
47682
|
Author |
Tatebe H, Murayama S, Yonekura T, Hatano T, Richter D, Furuya T, Kataoka S, Furuita K, Kojima C, Shiozaki K.
|
Title |
Substrate specificity of TOR complex 2 is determined by a ubiquitin-fold domain of the Sin1 subunit.
|
Journal |
Elife
|
Abstract |
The target of rapamycin (TOR) protein kinase forms multi-subunit TOR complex 1 (TORC1) and TOR complex 2 (TORC2), which exhibit distinct substrate specificities. Sin1 is one of the TORC2-specific subunit essential for phosphorylation and activation of certain AGC-family kinases. Here, we show that Sin1 is dispensable for the catalytic activity of TORC2, but its conserved region in the middle (Sin1CRIM) forms a discrete domain that specifically binds the TORC2 substrate kinases. Sin1CRIM fused to a different TORC2 subunit can recruit the TORC2 substrate Gad8 for phosphorylation even in the sin1 null mutant of fission yeast. The solution structure of Sin1CRIM shows a ubiquitin-like fold with a characteristic acidic loop, which is essential for interaction with the TORC2 substrates. The specific substrate-recognition function is conserved in human Sin1CRIM, which may represent a potential target for novel anticancer drugs that prevent activation of the mTORC2 substrates such as AKT.
|
Volume |
6
|
Published |
2017-3-7
|
DOI |
10.7554/eLife.19594
|
PII |
e19594
|
PMID |
28264193
|
PMC |
PMC5340527
|
MeSH |
Adaptor Proteins, Signal Transducing / chemistry
Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Carrier Proteins / chemistry*
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Conserved Sequence
HEK293 Cells
Humans
Magnetic Resonance Spectroscopy
Mechanistic Target of Rapamycin Complex 2 / metabolism*
Models, Molecular
Protein Binding
Protein Conformation
Protein Folding
Protein Interaction Mapping
Schizosaccharomyces / enzymology
Schizosaccharomyces pombe Proteins / chemistry*
Schizosaccharomyces pombe Proteins / genetics
Schizosaccharomyces pombe Proteins / metabolism*
Substrate Specificity
|
IF |
7.08
|
Resource |
Yeast |
FYC550(psk1)? |
Human and Animal Cells |
MCF7(RCB1904)
293T(RCB2202) |