7owg

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human DEPTOR in a complex with mutant human mTORC1 A1459P

Structural highlights

7owg is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 4.7Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

MTOR_HUMAN Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals. Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2). Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E). Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B and the inhibitor of translation initiation PDCD4. Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 a RNA polymerase III-repressor. In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1. To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A. mTORC1 also negatively regulates autophagy through phosphorylation of ULK1. Under nutrient sufficiency, phosphorylates ULK1 at 'Ser-758', disrupting the interaction with AMPK and preventing activation of ULK1. Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP. mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor. Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules. As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton. Plays a critical role in the phosphorylation at 'Ser-473' of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1. mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B. mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422'.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16]

Publication Abstract from PubMed

The mTORC1 kinase complex regulates cell growth, proliferation, and survival. Because mis-regulation of DEPTOR, an endogenous mTORC1 inhibitor, is associated with some cancers, we reconstituted mTORC1 with DEPTOR to understand its function. We find that DEPTOR is a unique partial mTORC1 inhibitor that may have evolved to preserve feedback inhibition of PI3K. Counterintuitively, mTORC1 activated by RHEB or oncogenic mutation is much more potently inhibited by DEPTOR. Although DEPTOR partially inhibits mTORC1, mTORC1 prevents this inhibition by phosphorylating DEPTOR, a mutual antagonism that requires no exogenous factors. Structural analyses of the mTORC1/DEPTOR complex showed DEPTOR's PDZ domain interacting with the mTOR FAT region, and the unstructured linker preceding the PDZ binding to the mTOR FRB domain. The linker and PDZ form the minimal inhibitory unit, but the N-terminal tandem DEP domains also significantly contribute to inhibition.

Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace.,Heimhalt M, Berndt A, Wagstaff J, Anandapadamanaban M, Perisic O, Maslen S, McLaughlin S, Yu CW, Masson GR, Boland A, Ni X, Yamashita K, Murshudov GN, Skehel M, Freund SM, Williams RL Elife. 2021 Sep 14;10:e68799. doi: 10.7554/eLife.68799. PMID:34519269[17]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell. 2002 Jul 26;110(2):163-75. PMID:12150925
  2. ↑ Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S, Tokunaga C, Avruch J, Yonezawa K. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell. 2002 Jul 26;110(2):177-89. PMID:12150926
  3. ↑ Choi JH, Bertram PG, Drenan R, Carvalho J, Zhou HH, Zheng XF. The FKBP12-rapamycin-associated protein (FRAP) is a CLIP-170 kinase. EMBO Rep. 2002 Oct;3(10):988-94. Epub 2002 Sep 13. PMID:12231510 doi:10.1093/embo-reports/kvf197
  4. ↑ Park IH, Bachmann R, Shirazi H, Chen J. Regulation of ribosomal S6 kinase 2 by mammalian target of rapamycin. J Biol Chem. 2002 Aug 30;277(35):31423-9. Epub 2002 Jun 26. PMID:12087098 doi:10.1074/jbc.M204080200
  5. ↑ Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003 Nov 26;115(5):577-90. PMID:14651849
  6. ↑ Kim DH, Sarbassov DD, Ali SM, Latek RR, Guntur KV, Erdjument-Bromage H, Tempst P, Sabatini DM. GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR. Mol Cell. 2003 Apr;11(4):895-904. PMID:12718876
  7. ↑ Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 2004 Jul 27;14(14):1296-302. PMID:15268862 doi:10.1016/j.cub.2004.06.054
  8. ↑ Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG Jr. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev. 2004 Dec 1;18(23):2893-904. Epub 2004 Nov 15. PMID:15545625 doi:10.1101/gad.1256804
  9. ↑ Jacinto E, Loewith R, Schmidt A, Lin S, Ruegg MA, Hall A, Hall MN. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004 Nov;6(11):1122-8. Epub 2004 Oct 3. PMID:15467718 doi:10.1038/ncb1183
  10. ↑ Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science. 2005 Feb 18;307(5712):1098-101. PMID:15718470 doi:307/5712/1098
  11. ↑ Garcia-Martinez JM, Alessi DR. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J. 2008 Dec 15;416(3):375-85. doi: 10.1042/BJ20081668. PMID:18925875 doi:10.1042/BJ20081668
  12. ↑ Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S, Griffiths JR, Chung YL, Schulze A. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 2008 Sep;8(3):224-36. doi: 10.1016/j.cmet.2008.07.007. PMID:18762023 doi:10.1016/j.cmet.2008.07.007
  13. ↑ Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science. 2008 Jun 13;320(5882):1496-501. doi: 10.1126/science.1157535. Epub 2008 , May 22. PMID:18497260 doi:10.1126/science.1157535
  14. ↑ Koren I, Reem E, Kimchi A. DAP1, a novel substrate of mTOR, negatively regulates autophagy. Curr Biol. 2010 Jun 22;20(12):1093-8. doi: 10.1016/j.cub.2010.04.041. Epub 2010, May 27. PMID:20537536 doi:10.1016/j.cub.2010.04.041
  15. ↑ Michels AA, Robitaille AM, Buczynski-Ruchonnet D, Hodroj W, Reina JH, Hall MN, Hernandez N. mTORC1 directly phosphorylates and regulates human MAF1. Mol Cell Biol. 2010 Aug;30(15):3749-57. doi: 10.1128/MCB.00319-10. Epub 2010 Jun , 1. PMID:20516213 doi:10.1128/MCB.00319-10
  16. ↑ Hsu PP, Kang SA, Rameseder J, Zhang Y, Ottina KA, Lim D, Peterson TR, Choi Y, Gray NS, Yaffe MB, Marto JA, Sabatini DM. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science. 2011 Jun 10;332(6035):1317-22. doi: 10.1126/science.1199498. PMID:21659604 doi:10.1126/science.1199498
  17. ↑ Heimhalt M, Berndt A, Wagstaff J, Anandapadamanaban M, Perisic O, Maslen S, McLaughlin S, Yu CW, Masson GR, Boland A, Ni X, Yamashita K, Murshudov GN, Skehel M, Freund SM, Williams RL. Bipartite binding and partial inhibition links DEPTOR and mTOR in a mutually antagonistic embrace. Elife. 2021 Sep 14;10:e68799. PMID:34519269 doi:10.7554/eLife.68799

Contents


PDB ID 7owg

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