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| | ==Crystal structure of the Arabidopsis thaliana Raptor in complex with the TOS peptide of human PRAS40== | | ==Crystal structure of the Arabidopsis thaliana Raptor in complex with the TOS peptide of human PRAS40== |
| - | <StructureSection load='5wbl' size='340' side='right' caption='[[5wbl]], [[Resolution|resolution]] 3.35Å' scene=''> | + | <StructureSection load='5wbl' size='340' side='right'caption='[[5wbl]], [[Resolution|resolution]] 3.35Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5wbl]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Arath Arath]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WBL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WBL FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5wbl]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Arabidopsis_thaliana Arabidopsis thaliana] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WBL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5WBL FirstGlance]. <br> |
| - | </td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">RAPTOR1, RAPTOR1B, At3g08850, T16O11.22 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=3702 ARATH])</td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.35Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5wbl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wbl OCA], [http://pdbe.org/5wbl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wbl RCSB], [http://www.ebi.ac.uk/pdbsum/5wbl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wbl ProSAT]</span></td></tr> | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5wbl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wbl OCA], [https://pdbe.org/5wbl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5wbl RCSB], [https://www.ebi.ac.uk/pdbsum/5wbl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5wbl ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/RTOR1_ARATH RTOR1_ARATH]] Probable component of the plant TOR kinase pathway that recruits substrates for TOR. Modulates plant cell growth and regulates the activity of ATPK1 kinase in response to osmotic stress.<ref>PMID:16377759</ref> [[http://www.uniprot.org/uniprot/AKTS1_HUMAN AKTS1_HUMAN]] Subunit of mTORC1, which regulates cell growth and survival in response to nutrient and hormonal signals. mTORC1 is activated in response to growth factors or amino acids. Growth factor-stimulated mTORC1 activation involves a AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase that potently activates the protein kinase activity of mTORC1. Amino acid-signaling to mTORC1 requires its relocalization to the lysosomes mediated by the Ragulator complex and the Rag GTPases. Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from inhibiting the elongation initiation factor 4E (eiF4E). mTORC1 phosphorylates and activates S6K1 at 'Thr-389', which then promotes protein synthesis by phosphorylating PDCD4 and targeting it for degradation. Within mTORC1, AKT1S1 negatively regulates mTOR activity in a manner that is dependent on its phosphorylation state and binding to 14-3-3 proteins. Inhibits RHEB-GTP-dependent mTORC1 activation. Substrate for AKT1 phosphorylation, but can also be activated by AKT1-independent mechanisms. May also play a role in nerve growth factor-mediated neuroprotection.<ref>PMID:16174443</ref> <ref>PMID:17277771</ref> <ref>PMID:17386266</ref> | + | [https://www.uniprot.org/uniprot/AKTS1_HUMAN AKTS1_HUMAN] Subunit of mTORC1, which regulates cell growth and survival in response to nutrient and hormonal signals. mTORC1 is activated in response to growth factors or amino acids. Growth factor-stimulated mTORC1 activation involves a AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase that potently activates the protein kinase activity of mTORC1. Amino acid-signaling to mTORC1 requires its relocalization to the lysosomes mediated by the Ragulator complex and the Rag GTPases. Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from inhibiting the elongation initiation factor 4E (eiF4E). mTORC1 phosphorylates and activates S6K1 at 'Thr-389', which then promotes protein synthesis by phosphorylating PDCD4 and targeting it for degradation. Within mTORC1, AKT1S1 negatively regulates mTOR activity in a manner that is dependent on its phosphorylation state and binding to 14-3-3 proteins. Inhibits RHEB-GTP-dependent mTORC1 activation. Substrate for AKT1 phosphorylation, but can also be activated by AKT1-independent mechanisms. May also play a role in nerve growth factor-mediated neuroprotection.<ref>PMID:16174443</ref> <ref>PMID:17277771</ref> <ref>PMID:17386266</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5wbl" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5wbl" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Raptor|Raptor]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Arath]] | + | [[Category: Arabidopsis thaliana]] |
| - | [[Category: Jiang, X]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Pavletich, N P]] | + | [[Category: Large Structures]] |
| - | [[Category: Protein binding]] | + | [[Category: Jiang X]] |
| - | [[Category: Raptor]] | + | [[Category: Pavletich NP]] |
| - | [[Category: To]]
| + | |
| Structural highlights
Function
AKTS1_HUMAN Subunit of mTORC1, which regulates cell growth and survival in response to nutrient and hormonal signals. mTORC1 is activated in response to growth factors or amino acids. Growth factor-stimulated mTORC1 activation involves a AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase that potently activates the protein kinase activity of mTORC1. Amino acid-signaling to mTORC1 requires its relocalization to the lysosomes mediated by the Ragulator complex and the Rag GTPases. Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from inhibiting the elongation initiation factor 4E (eiF4E). mTORC1 phosphorylates and activates S6K1 at 'Thr-389', which then promotes protein synthesis by phosphorylating PDCD4 and targeting it for degradation. Within mTORC1, AKT1S1 negatively regulates mTOR activity in a manner that is dependent on its phosphorylation state and binding to 14-3-3 proteins. Inhibits RHEB-GTP-dependent mTORC1 activation. Substrate for AKT1 phosphorylation, but can also be activated by AKT1-independent mechanisms. May also play a role in nerve growth factor-mediated neuroprotection.[1] [2] [3]
Publication Abstract from PubMed
The mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth and metabolism in response to nutrients, energy levels, and growth factors. It contains the atypical kinase mTOR and the RAPTOR subunit that binds to the Tor signalling sequence (TOS) motif of substrates and regulators. mTORC1 is activated by the small GTPase RHEB (Ras homologue enriched in brain) and inhibited by PRAS40. Here we present the 3.0 angstrom cryo-electron microscopy structure of mTORC1 and the 3.4 angstrom structure of activated RHEB-mTORC1. RHEB binds to mTOR distally from the kinase active site, yet causes a global conformational change that allosterically realigns active-site residues, accelerating catalysis. Cancer-associated hyperactivating mutations map to structural elements that maintain the inactive state, and we provide biochemical evidence that they mimic RHEB relieving auto-inhibition. We also present crystal structures of RAPTOR-TOS motif complexes that define the determinants of TOS recognition, of an mTOR FKBP12-rapamycin-binding (FRB) domain-substrate complex that establishes a second substrate-recruitment mechanism, and of a truncated mTOR-PRAS40 complex that reveals PRAS40 inhibits both substrate-recruitment sites. These findings help explain how mTORC1 selects its substrates, how its kinase activity is controlled, and how it is activated by cancer-associated mutations.
Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40.,Yang H, Jiang X, Li B, Yang HJ, Miller M, Yang A, Dhar A, Pavletich NP Nature. 2017 Dec 13. pii: nature25023. doi: 10.1038/nature25023. PMID:29236692[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Huang B, Porter G. Expression of proline-rich Akt-substrate PRAS40 in cell survival pathway and carcinogenesis. Acta Pharmacol Sin. 2005 Oct;26(10):1253-8. doi:, 10.1111/j.1745-7254.2005.00184.x. PMID:16174443 doi:http://dx.doi.org/10.1111/j.1745-7254.2005.00184.x
- ↑ Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol. 2007 Mar;9(3):316-23. doi: 10.1038/ncb1547. Epub 2007 Feb 4. PMID:17277771 doi:http://dx.doi.org/10.1038/ncb1547
- ↑ Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, Spooner E, Carr SA, Sabatini DM. PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell. 2007 Mar 23;25(6):903-15. doi: 10.1016/j.molcel.2007.03.003. PMID:17386266 doi:http://dx.doi.org/10.1016/j.molcel.2007.03.003
- ↑ Yang H, Jiang X, Li B, Yang HJ, Miller M, Yang A, Dhar A, Pavletich NP. Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Nature. 2017 Dec 13. pii: nature25023. doi: 10.1038/nature25023. PMID:29236692 doi:http://dx.doi.org/10.1038/nature25023
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