3a62

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of phosphorylated p70S6K1

Structural highlights

3a62 is a 1 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:	X-ray diffraction, Resolution 2.35Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

KS6B1_HUMAN Serine/threonine-protein kinase that acts downstream of mTOR signaling in response to growth factors and nutrients to promote cell proliferation, cell growth and cell cycle progression. Regulates protein synthesis through phosphorylation of EIF4B, RPS6 and EEF2K, and contributes to cell survival by repressing the pro-apoptotic function of BAD. Under conditions of nutrient depletion, the inactive form associates with the EIF3 translation initiation complex. Upon mitogenic stimulation, phosphorylation by the mammalian target of rapamycin complex 1 (mTORC1) leads to dissociation from the EIF3 complex and activation. The active form then phosphorylates and activates several substrates in the preinitiation complex, including the EIF2B complex and the cap-binding complex component EIF4B. Also controls translation initiation by phosphorylating a negative regulator of EIF4A, PDCD4, targeting it for ubiquitination and subsequent proteolysis. Promotes initiation of the pioneer round of protein synthesis by phosphorylating POLDIP3/SKAR. In response to IGF1, activates translation elongation by phosphorylating EEF2 kinase (EEF2K), which leads to its inhibition and thus activation of EEF2. Also plays a role in feedback regulation of mTORC2 by mTORC1 by phosphorylating RICTOR, resulting in the inhibition of mTORC2 and AKT1 signaling. Mediates cell survival by phosphorylating the pro-apoptotic protein BAD and suppressing its pro-apoptotic function. Phosphorylates mitochondrial URI1 leading to dissociation of a URI1-PPP1CC complex. The free mitochondrial PPP1CC can then dephosphorylate RPS6KB1 at 'Thr-412', which is proposed to be a negative feedback mechanism for the RPS6KB1 anti-apoptotic function. Mediates TNF-alpha-induced insulin resistance by phosphorylating IRS1 at multiple serine residues, resulting in accelerated degradation of IRS1. In cells lacking functional TSC1-2 complex, constitutively phosphorylates and inhibits GSK3B. May be involved in cytoskeletal rearrangement through binding to neurabin.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11] ^[12] ^[13] ^[14]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

p70 ribosomal S6 kinase (p70S6K) is a downstream effector of the mTOR signaling pathway involved in cell proliferation, cell growth, cell-cycle progression, and glucose homeostasis. Multiple phosphorylation events within the catalytic, autoinhibitory, and hydrophobic motif domains contribute to the regulation of p70S6K. We report the crystal structures of the kinase domain of p70S6K1 bound to staurosporine in both the unphosphorylated state and in the 3'-phosphoinositide-dependent kinase-1-phosphorylated state in which Thr-252 of the activation loop is phosphorylated. Unphosphorylated p70S6K1 exists in two crystal forms, one in which the p70S6K1 kinase domain exists as a monomer and the other as a domain-swapped dimer. The crystal structure of the partially activated kinase domain that is phosphorylated within the activation loop reveals conformational ordering of the activation loop that is consistent with a role in activation. The structures offer insights into the structural basis of the 3'-phosphoinositide-dependent kinase-1-induced activation of p70S6K and provide a platform for the rational structure-guided design of specific p70S6K inhibitors.

Structural basis of human p70 ribosomal S6 kinase-1 regulation by activation loop phosphorylation.,Sunami T, Byrne N, Diehl RE, Funabashi K, Hall DL, Ikuta M, Patel SB, Shipman JM, Smith RF, Takahashi I, Zugay-Murphy J, Iwasawa Y, Lumb KJ, Munshi SK, Sharma S J Biol Chem. 2010 Feb 12;285(7):4587-94. Epub 2009 Oct 28. PMID:19864428^[15]

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

References

↑ Wang X, Li W, Williams M, Terada N, Alessi DR, Proud CG. Regulation of elongation factor 2 kinase by p90(RSK1) and p70 S6 kinase. EMBO J. 2001 Aug 15;20(16):4370-9. PMID:11500364 doi:http://dx.doi.org/10.1093/emboj/20.16.4370
↑ Fleckenstein DS, Dirks WG, Drexler HG, Quentmeier H. Tumor necrosis factor receptor-associated factor (TRAF) 4 is a new binding partner for the p70S6 serine/threonine kinase. Leuk Res. 2003 Aug;27(8):687-94. PMID:12801526
↑ Richardson CJ, Broenstrup M, Fingar DC, Julich K, Ballif BA, Gygi S, Blenis J. SKAR is a specific target of S6 kinase 1 in cell growth control. Curr Biol. 2004 Sep 7;14(17):1540-9. PMID:15341740 doi:http://dx.doi.org/10.1016/j.cub.2004.08.061
↑ Raught B, Peiretti F, Gingras AC, Livingstone M, Shahbazian D, Mayeur GL, Polakiewicz RD, Sonenberg N, Hershey JW. Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases. EMBO J. 2004 Apr 21;23(8):1761-9. Epub 2004 Apr 8. PMID:15071500 doi:http://dx.doi.org/10.1038/sj.emboj.7600193
↑ Fingar DC, Richardson CJ, Tee AR, Cheatham L, Tsou C, Blenis J. mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol. 2004 Jan;24(1):200-16. PMID:14673156
↑ Holz MK, Ballif BA, Gygi SP, Blenis J. mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events. Cell. 2005 Nov 18;123(4):569-80. PMID:16286006 doi:http://dx.doi.org/S0092-8674(05)01157-8
↑ Zhang HH, Lipovsky AI, Dibble CC, Sahin M, Manning BD. S6K1 regulates GSK3 under conditions of mTOR-dependent feedback inhibition of Akt. Mol Cell. 2006 Oct 20;24(2):185-97. PMID:17052453 doi:http://dx.doi.org/10.1016/j.molcel.2006.09.019
↑ Dorrello NV, Peschiaroli A, Guardavaccaro D, Colburn NH, Sherman NE, Pagano M. S6K1- and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science. 2006 Oct 20;314(5798):467-71. PMID:17053147 doi:10.1126/science.1130276
↑ Djouder N, Metzler SC, Schmidt A, Wirbelauer C, Gstaiger M, Aebersold R, Hess D, Krek W. S6K1-mediated disassembly of mitochondrial URI/PP1gamma complexes activates a negative feedback program that counters S6K1 survival signaling. Mol Cell. 2007 Oct 12;28(1):28-40. PMID:17936702 doi:http://dx.doi.org/10.1016/j.molcel.2007.08.010
↑ Zhang J, Gao Z, Yin J, Quon MJ, Ye J. S6K directly phosphorylates IRS-1 on Ser-270 to promote insulin resistance in response to TNF-(alpha) signaling through IKK2. J Biol Chem. 2008 Dec 19;283(51):35375-82. doi: 10.1074/jbc.M806480200. Epub 2008, Oct 24. PMID:18952604 doi:http://dx.doi.org/10.1074/jbc.M806480200
↑ Kim D, Akcakanat A, Singh G, Sharma C, Meric-Bernstam F. Regulation and localization of ribosomal protein S6 kinase 1 isoforms. Growth Factors. 2009 Feb;27(1):12-21. doi: 10.1080/08977190802556986. PMID:19085255 doi:http://dx.doi.org/10.1080/08977190802556986
↑ Dibble CC, Asara JM, Manning BD. Characterization of Rictor phosphorylation sites reveals direct regulation of mTOR complex 2 by S6K1. Mol Cell Biol. 2009 Nov;29(21):5657-70. Epub 2009 Aug 31. PMID:19720745 doi:http://dx.doi.org/MCB.00735-09
↑ Julien LA, Carriere A, Moreau J, Roux PP. mTORC1-activated S6K1 phosphorylates Rictor on threonine 1135 and regulates mTORC2 signaling. Mol Cell Biol. 2010 Feb;30(4):908-21. doi: 10.1128/MCB.00601-09. Epub 2009 Dec 7. PMID:19995915 doi:http://dx.doi.org/10.1128/MCB.00601-09
↑ Treins C, Warne PH, Magnuson MA, Pende M, Downward J. Rictor is a novel target of p70 S6 kinase-1. Oncogene. 2010 Feb 18;29(7):1003-16. doi: 10.1038/onc.2009.401. Epub 2009 Nov 23. PMID:19935711 doi:http://dx.doi.org/10.1038/onc.2009.401
↑ Sunami T, Byrne N, Diehl RE, Funabashi K, Hall DL, Ikuta M, Patel SB, Shipman JM, Smith RF, Takahashi I, Zugay-Murphy J, Iwasawa Y, Lumb KJ, Munshi SK, Sharma S. Structural basis of human p70 ribosomal S6 kinase-1 regulation by activation loop phosphorylation. J Biol Chem. 2010 Feb 12;285(7):4587-94. Epub 2009 Oct 28. PMID:19864428 doi:10.1074/jbc.M109.040667

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3a62"

@@ Line 3: / Line 3: @@
 <StructureSection load='3a62' size='340' side='right'caption='[[3a62]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3a62]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3A62 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=3A62 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3a62]] is a 1 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=3A62 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3A62 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=STU:STAUROSPORINE'>STU</scene></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]] 2.35&#8491;</td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=STU:STAUROSPORINE'>STU</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3a60|3a60]], [[3a61|3a61]]</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=3a62 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3a62 OCA], [https://pdbe.org/3a62 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3a62 RCSB], [https://www.ebi.ac.uk/pdbsum/3a62 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3a62 ProSAT]</span></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=3a62 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3a62 OCA], [http://pdbe.org/3a62 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3a62 RCSB], [http://www.ebi.ac.uk/pdbsum/3a62 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3a62 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/KS6B1_HUMAN KS6B1_HUMAN]] Serine/threonine-protein kinase that acts downstream of mTOR signaling in response to growth factors and nutrients to promote cell proliferation, cell growth and cell cycle progression. Regulates protein synthesis through phosphorylation of EIF4B, RPS6 and EEF2K, and contributes to cell survival by repressing the pro-apoptotic function of BAD. Under conditions of nutrient depletion, the inactive form associates with the EIF3 translation initiation complex. Upon mitogenic stimulation, phosphorylation by the mammalian target of rapamycin complex 1 (mTORC1) leads to dissociation from the EIF3 complex and activation. The active form then phosphorylates and activates several substrates in the preinitiation complex, including the EIF2B complex and the cap-binding complex component EIF4B. Also controls translation initiation by phosphorylating a negative regulator of EIF4A, PDCD4, targeting it for ubiquitination and subsequent proteolysis. Promotes initiation of the pioneer round of protein synthesis by phosphorylating POLDIP3/SKAR. In response to IGF1, activates translation elongation by phosphorylating EEF2 kinase (EEF2K), which leads to its inhibition and thus activation of EEF2. Also plays a role in feedback regulation of mTORC2 by mTORC1 by phosphorylating RICTOR, resulting in the inhibition of mTORC2 and AKT1 signaling. Mediates cell survival by phosphorylating the pro-apoptotic protein BAD and suppressing its pro-apoptotic function. Phosphorylates mitochondrial URI1 leading to dissociation of a URI1-PPP1CC complex. The free mitochondrial PPP1CC can then dephosphorylate RPS6KB1 at 'Thr-412', which is proposed to be a negative feedback mechanism for the RPS6KB1 anti-apoptotic function. Mediates TNF-alpha-induced insulin resistance by phosphorylating IRS1 at multiple serine residues, resulting in accelerated degradation of IRS1. In cells lacking functional TSC1-2 complex, constitutively phosphorylates and inhibits GSK3B. May be involved in cytoskeletal rearrangement through binding to neurabin.<ref>PMID:11500364</ref> <ref>PMID:12801526</ref> <ref>PMID:15341740</ref> <ref>PMID:15071500</ref> <ref>PMID:14673156</ref> <ref>PMID:16286006</ref> <ref>PMID:17052453</ref> <ref>PMID:17053147</ref> <ref>PMID:17936702</ref> <ref>PMID:18952604</ref> <ref>PMID:19085255</ref> <ref>PMID:19720745</ref> <ref>PMID:19995915</ref> <ref>PMID:19935711</ref>
+[https://www.uniprot.org/uniprot/KS6B1_HUMAN KS6B1_HUMAN] Serine/threonine-protein kinase that acts downstream of mTOR signaling in response to growth factors and nutrients to promote cell proliferation, cell growth and cell cycle progression. Regulates protein synthesis through phosphorylation of EIF4B, RPS6 and EEF2K, and contributes to cell survival by repressing the pro-apoptotic function of BAD. Under conditions of nutrient depletion, the inactive form associates with the EIF3 translation initiation complex. Upon mitogenic stimulation, phosphorylation by the mammalian target of rapamycin complex 1 (mTORC1) leads to dissociation from the EIF3 complex and activation. The active form then phosphorylates and activates several substrates in the preinitiation complex, including the EIF2B complex and the cap-binding complex component EIF4B. Also controls translation initiation by phosphorylating a negative regulator of EIF4A, PDCD4, targeting it for ubiquitination and subsequent proteolysis. Promotes initiation of the pioneer round of protein synthesis by phosphorylating POLDIP3/SKAR. In response to IGF1, activates translation elongation by phosphorylating EEF2 kinase (EEF2K), which leads to its inhibition and thus activation of EEF2. Also plays a role in feedback regulation of mTORC2 by mTORC1 by phosphorylating RICTOR, resulting in the inhibition of mTORC2 and AKT1 signaling. Mediates cell survival by phosphorylating the pro-apoptotic protein BAD and suppressing its pro-apoptotic function. Phosphorylates mitochondrial URI1 leading to dissociation of a URI1-PPP1CC complex. The free mitochondrial PPP1CC can then dephosphorylate RPS6KB1 at 'Thr-412', which is proposed to be a negative feedback mechanism for the RPS6KB1 anti-apoptotic function. Mediates TNF-alpha-induced insulin resistance by phosphorylating IRS1 at multiple serine residues, resulting in accelerated degradation of IRS1. In cells lacking functional TSC1-2 complex, constitutively phosphorylates and inhibits GSK3B. May be involved in cytoskeletal rearrangement through binding to neurabin.<ref>PMID:11500364</ref> <ref>PMID:12801526</ref> <ref>PMID:15341740</ref> <ref>PMID:15071500</ref> <ref>PMID:14673156</ref> <ref>PMID:16286006</ref> <ref>PMID:17052453</ref> <ref>PMID:17053147</ref> <ref>PMID:17936702</ref> <ref>PMID:18952604</ref> <ref>PMID:19085255</ref> <ref>PMID:19720745</ref> <ref>PMID:19995915</ref> <ref>PMID:19935711</ref>
 == Evolutionary Conservation ==
 [[Image:Consurf_key_small.gif|200px|right]]
@@ Line 17: / Line 15: @@
   <jmolCheckbox>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/a6/3a62_consurf.spt"</scriptWhenChecked>
-    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
+    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
@@ Line 33: / Line 31: @@
 ==See Also==
-*[[Ribosomal protein S6 kinase|Ribosomal protein S6 kinase]]
+*[[Ribosomal protein S6 kinase 3D structures|Ribosomal protein S6 kinase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Non-specific serine/threonine protein kinase]]
+[[Category: Byrne N]]
-[[Category: Byrne, N]]
+[[Category: Diehl RE]]
-[[Category: Diehl, R E]]
+[[Category: Funabashi K]]
-[[Category: Funabashi, K]]
+[[Category: Hall DL]]
-[[Category: Hall, D L]]
+[[Category: Ikuta M]]
-[[Category: Ikuta, M]]
+[[Category: Iwasawa Y]]
-[[Category: Iwasawa, Y]]
+[[Category: Lumb KJ]]
-[[Category: Lumb, K J]]
+[[Category: Munshi SK]]
-[[Category: Munshi, S K]]
+[[Category: Patel SB]]
-[[Category: Patel, S B]]
+[[Category: Sharma S]]
-[[Category: Sharma, S]]
+[[Category: Shipman JM]]
-[[Category: Shipman, J M]]
+[[Category: Smith RF]]
-[[Category: Smith, R F]]
+[[Category: Sunami T]]
-[[Category: Sunami, T]]
+[[Category: Takahashi I]]
-[[Category: Takahashi, I]]
+[[Category: Zugay-Murphy J]]
-[[Category: Zugay-Murphy, J]]
-[[Category: Activation]]
-[[Category: Active]]
-[[Category: Alternative initiation]]
-[[Category: Atp-binding]]
-[[Category: Cell junction]]
-[[Category: Cytoplasm]]
-[[Category: Inactive]]
-[[Category: Kinase]]
-[[Category: Kinase domain]]
-[[Category: Nucleotide-binding]]
-[[Category: Phosphoprotein]]
-[[Category: Polymorphism]]
-[[Category: Ribosomal s6 kinase]]
-[[Category: Serine/threonine-protein kinase]]
-[[Category: Synapse]]
-[[Category: Synaptosome]]
-[[Category: Transferase]]

3a62

From Proteopedia

Current revision

Crystal structure of phosphorylated p70S6K1

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

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Proteopedia Page Contributors and Editors (what is this?)

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