Substrate specificity of tor complex 2 is determined by a ubiquitin-fold domain of the sin1 subunit

Hisashi Tatebe, Shinichi Murayama, Toshiya Yonekura, Tomoyuki Hatano, David Richter, Tomomi Furuya, Saori Kataoka, Kyoko Furuita, Chojiro Kojima, Kazuhiro Shiozaki

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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.

Original languageEnglish (US)
Article numbere19594
JournaleLife
Volume6
DOIs
StatePublished - Mar 7 2017

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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