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Elife. 2017 Mar 7;6. pii: e19594. doi: 10.7554/eLife.19594.

Substrate specificity of TOR complex 2 is determined by a ubiquitin-fold domain of the Sin1 subunit.

Author information

1
Graduate School of Biological Sciences, Nara Institute of Science and Technology, Nara, Japan.
2
Department of Microbiology and Molecular Genetics, University of California, California, United States.
3
Institute for Protein Research, Osaka University, Osaka, Japan.
4
Graduate School of Engineering, Yokohama National University, Yokohama, Japan.

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.

KEYWORDS:

AKT; S. pombe; SIN1; TOR complex 2; biochemistry; cell biology; human; substrate specificity; target of rapamycin

PMID:
28264193
PMCID:
PMC5340527
DOI:
10.7554/eLife.19594
[Indexed for MEDLINE]
Free PMC Article

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