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| | ==Crystal structure of the pleckstrin homology domain of human Sin1, a TORC2 subunit== | | ==Crystal structure of the pleckstrin homology domain of human Sin1, a TORC2 subunit== |
| - | <StructureSection load='3voq' size='340' side='right' caption='[[3voq]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='3voq' size='340' side='right'caption='[[3voq]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3voq]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3VOQ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3VOQ FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3voq]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3VOQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3VOQ FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3ulb|3ulb]], [[3ulc|3ulc]]</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]] 2Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">SIN1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=3voq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3voq OCA], [https://pdbe.org/3voq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3voq RCSB], [https://www.ebi.ac.uk/pdbsum/3voq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3voq ProSAT]</span></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=3voq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3voq OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3voq RCSB], [http://www.ebi.ac.uk/pdbsum/3voq PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/SIN1_HUMAN SIN1_HUMAN]] Subunit of mTORC2, which regulates cell growth and survival in response to hormonal signals. mTORC2 is activated by growth factors, but, in contrast to mTORC1, seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'. Within mTORC2, MAPKAP1 is required for complex formation and mTORC2 kinase activity. MAPKAP1 inhibits MAP3K2 by preventing its dimerization and autophosphorylation. Inhibits HRAS and KRAS signaling. Enhances osmotic stress-induced phosphorylation of ATF2 and ATF2-mediated transcription.<ref>PMID:15988011</ref> <ref>PMID:16962653</ref> <ref>PMID:17054722</ref> <ref>PMID:17043309</ref> <ref>PMID:17303383</ref> | + | [https://www.uniprot.org/uniprot/SIN1_HUMAN SIN1_HUMAN] Subunit of mTORC2, which regulates cell growth and survival in response to hormonal signals. mTORC2 is activated by growth factors, but, in contrast to mTORC1, seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'. Within mTORC2, MAPKAP1 is required for complex formation and mTORC2 kinase activity. MAPKAP1 inhibits MAP3K2 by preventing its dimerization and autophosphorylation. Inhibits HRAS and KRAS signaling. Enhances osmotic stress-induced phosphorylation of ATF2 and ATF2-mediated transcription.<ref>PMID:15988011</ref> <ref>PMID:16962653</ref> <ref>PMID:17054722</ref> <ref>PMID:17043309</ref> <ref>PMID:17303383</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 3voq" style="background-color:#fffaf0;"></div> |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Matsuura, Y]] | + | [[Category: Large Structures]] |
| - | [[Category: Pan, D]] | + | [[Category: Matsuura Y]] |
| - | [[Category: Membrane protein]] | + | [[Category: Pan D]] |
| - | [[Category: Ph domain]]
| + | |
| Structural highlights
Function
SIN1_HUMAN Subunit of mTORC2, which regulates cell growth and survival in response to hormonal signals. mTORC2 is activated by growth factors, but, in contrast to mTORC1, seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'. Within mTORC2, MAPKAP1 is required for complex formation and mTORC2 kinase activity. MAPKAP1 inhibits MAP3K2 by preventing its dimerization and autophosphorylation. Inhibits HRAS and KRAS signaling. Enhances osmotic stress-induced phosphorylation of ATF2 and ATF2-mediated transcription.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
In eukaryotes, multiprotein complexes termed TOR complex 1 (TORC1) and TOR complex 2 (TORC2) function as major regulators of cell growth, metabolism and ageing. The C-terminal domain of the Saccharomyces cerevisiae TORC2 component Avo1 is required for plasma-membrane localization of TORC2 and is essential for yeast viability. X-ray crystal structures of the C-terminal domain of Avo1 and of its human orthologue Sin1 have been determined. The structures show that the C-termini of Avo1 and Sin1 both have the pleckstrin homology (PH) domain fold. Comparison with known PH-domain structures suggests a putative binding site for phosphoinositides.
Structures of the pleckstrin homology domain of Saccharomyces cerevisiae Avo1 and its human orthologue Sin1, an essential subunit of TOR complex 2.,Pan D, Matsuura Y Acta Crystallogr Sect F Struct Biol Cryst Commun. 2012 Apr 1;68(Pt 4):386-92., Epub 2012 Mar 27. PMID:22505404[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Cheng J, Zhang D, Kim K, Zhao Y, Zhao Y, Su B. Mip1, an MEKK2-interacting protein, controls MEKK2 dimerization and activation. Mol Cell Biol. 2005 Jul;25(14):5955-64. PMID:15988011 doi:25/14/5955
- ↑ Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, Huang Q, Qin J, Su B. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell. 2006 Oct 6;127(1):125-37. Epub 2006 Sep 7. PMID:16962653 doi:S0092-8674(06)01147-0
- ↑ Makino C, Sano Y, Shinagawa T, Millar JB, Ishii S. Sin1 binds to both ATF-2 and p38 and enhances ATF-2-dependent transcription in an SAPK signaling pathway. Genes Cells. 2006 Nov;11(11):1239-51. PMID:17054722 doi:GTC1016
- ↑ Yang Q, Inoki K, Ikenoue T, Guan KL. Identification of Sin1 as an essential TORC2 component required for complex formation and kinase activity. Genes Dev. 2006 Oct 15;20(20):2820-32. PMID:17043309 doi:10.1101/gad.1461206
- ↑ Schroder WA, Buck M, Cloonan N, Hancock JF, Suhrbier A, Sculley T, Bushell G. Human Sin1 contains Ras-binding and pleckstrin homology domains and suppresses Ras signalling. Cell Signal. 2007 Jun;19(6):1279-89. Epub 2007 Jan 20. PMID:17303383 doi:10.1016/j.cellsig.2007.01.013
- ↑ Pan D, Matsuura Y. Structures of the pleckstrin homology domain of Saccharomyces cerevisiae Avo1 and its human orthologue Sin1, an essential subunit of TOR complex 2. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2012 Apr 1;68(Pt 4):386-92., Epub 2012 Mar 27. PMID:22505404 doi:10.1107/S1744309112007178
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