Journal
ELIFE
Volume 6, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.19594
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Funding
- National Institute of General Medical Sciences [GM059788]
- Japan Society for the Promotion of Science [23870019, 26291024, 16K14681, 26291013, 23770230, 25440086]
- Ministry of Education, Culture,Sports, Science, and Technology
- Japan Agency for Medical Research and Development
- Mitsubishi Foundation
- Daiichi Sankyo Foundation of Life Science
- Astellas Foundation for Research on Metabolic Disorders
- Sagawa Foundation for Promotion of Cancer Research
- Foundation for NAIST
- Grants-in-Aid for Scientific Research [23870019, 25440086, 16K14681, 26291013, 26291024, 23770230] Funding Source: KAKEN
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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.
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