title: Substrate specificity of TOR complex 2 is determined by a ubiquitin-fold domain of the Sin1 subunit.
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 thesin1null 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.
authors.affiliation: Graduate School of Biological Sciences, Nara Institute of Science and Technology, Nara, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Tatebe
authors.affiliation: Graduate School of Biological Sciences, Nara Institute of Science and Technology, Nara, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Murayama
authors.affiliation: Graduate School of Biological Sciences, Nara Institute of Science and Technology, Nara, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Yonekura
authors.affiliation: Graduate School of Biological Sciences, Nara Institute of Science and Technology, Nara, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Hatano
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, California, United States.
authors.forename: David
authors.initials: D
authors.lastname: Richter
authors.affiliation: Graduate School of Biological Sciences, Nara Institute of Science and Technology, Nara, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Furuya
authors.affiliation: Institute for Protein Research, Osaka University, Osaka, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Kataoka
authors.affiliation: Institute for Protein Research, Osaka University, Osaka, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Furuita
authors.affiliation: Institute for Protein Research, Osaka University, Osaka, Japan.|Graduate School of Engineering, Yokohama National University, Yokohama, Japan.
authors.forename: Chojiro
authors.initials: C
authors.lastname: Kojima
authors.affiliation: Graduate School of Biological Sciences, Nara Institute of Science and Technology, Nara, Japan.|Department of Microbiology and Molecular Genetics, University of California, California, United States.
authors.forename: Kazuhiro
authors.identifier: 0000-0002-0395-5457
authors.initials: K
authors.lastname: Shiozaki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017124:Conserved Sequence; D057809:HEK293 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D000076225:Mechanistic Target of Rapamycin Complex 2 / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D025941:Protein Interaction Mapping; D012568:Schizosaccharomyces / Q000201:enzymology; D029702:Schizosaccharomyces pombe Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C493277:MAPKAP1 protein, human; D029702:Schizosaccharomyces pombe Proteins; C000602849:Sin1 protein, S pombe; D000076225:Mechanistic Target of Rapamycin Complex 2
keywords: AKT; S. pombe; SIN1; TOR complex 2; biochemistry; cell biology; human; substrate specificity; target of rapamycin