2vki

From Proteopedia

(Difference between revisions)

Revision as of 04:47, 8 February 2016

STRUCTURE OF THE PDK1 PH DOMAIN K465E MUTANT

Structural highlights

2vki is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Related:	1uu8, 1oky, 1z5m, 1uu9, 1okz, 1w1d, 1h1w, 1uu3, 1w1g, 2biy, 1w1h, 1uu7, 1uvr
Activity:	Non-specific serine/threonine protein kinase, with EC number 2.7.11.1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum

Function

[PDPK1_HUMAN] Serine/threonine kinase which acts as a master kinase, phosphorylating and activating a subgroup of the AGC family of protein kinases. Its targets include: protein kinase B (PKB/AKT1, PKB/AKT2, PKB/AKT3), p70 ribosomal protein S6 kinase (RPS6KB1), p90 ribosomal protein S6 kinase (RPS6KA1, RPS6KA2 and RPS6KA3), cyclic AMP-dependent protein kinase (PRKACA), protein kinase C (PRKCD and PRKCZ), serum and glucocorticoid-inducible kinase (SGK1, SGK2 and SGK3), p21-activated kinase-1 (PAK1), protein kinase PKN (PKN1 and PKN2). Plays a central role in the transduction of signals from insulin by providing the activating phosphorylation to PKB/AKT1, thus propagating the signal to downstream targets controlling cell proliferation and survival, as well as glucose and amino acid uptake and storage. Negatively regulates the TGF-beta-induced signaling by: modulating the association of SMAD3 and SMAD7 with TGF-beta receptor, phosphorylating SMAD2, SMAD3, SMAD4 and SMAD7, preventing the nuclear translocation of SMAD3 and SMAD4 and the translocation of SMAD7 from the nucleus to the cytoplasm in response to TGF-beta. Activates PPARG transcriptional activity and promotes adipocyte differentiation. Activates the NF-kappa-B pathway via phosphorylation of IKKB. The tyrosine phosphorylated form is crucial for the regulation of focal adhesions by angiotensin II. Controls proliferation, survival, and growth of developing pancreatic cells. Participates in the regulation of Ca(2+) entry and Ca(2+)-activated K(+) channels of mast cells. Essential for the motility of vascular endothelial cells (ECs) and is involved in the regulation of their chemotaxis. Plays a critical role in cardiac homeostasis by serving as a dual effector for cell survival and beta-adrenergic response. Plays an important role during thymocyte development by regulating the expression of key nutrient receptors on the surface of pre-T cells and mediating Notch-induced cell growth and proliferative responses. Provides negative feedback inhibition to toll-like receptor-mediated NF-kappa-B activation in macrophages. Isoform 3 is catalytically inactive.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] ^[8] ^[9] ^[10] ^[11] ^[12] ^[13] ^[14] ^[15]

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

PDK1 activates a group of kinases, including protein kinase B (PKB)/Akt, p70 ribosomal S6 kinase (S6K), and serum and glucocorticoid-induced protein kinase (SGK), that mediate many of the effects of insulin as well as other agonists. PDK1 interacts with phosphoinositides through a pleckstrin homology (PH) domain. To study the role of this interaction, we generated knock-in mice expressing a mutant of PDK1 incapable of binding phosphoinositides. The knock-in mice are significantly small, insulin resistant, and hyperinsulinemic. Activation of PKB is markedly reduced in knock-in mice as a result of lower phosphorylation of PKB at Thr308, the residue phosphorylated by PDK1. This results in the inhibition of the downstream mTOR complex 1 and S6K1 signaling pathways. In contrast, activation of SGK1 or p90 ribosomal S6 kinase or stimulation of S6K1 induced by feeding is unaffected by the PDK1 PH domain mutation. These observations establish the importance of the PDK1-phosphoinositide interaction in enabling PKB to be efficiently activated with an animal model. Our findings reveal how reduced activation of PKB isoforms impinges on downstream signaling pathways, causing diminution of size as well as insulin resistance.

Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance.,Bayascas JR, Wullschleger S, Sakamoto K, Garcia-Martinez JM, Clacher C, Komander D, van Aalten DM, Boini KM, Lang F, Lipina C, Logie L, Sutherland C, Chudek JA, van Diepen JA, Voshol PJ, Lucocq JM, Alessi DR Mol Cell Biol. 2008 May;28(10):3258-72. Epub 2008 Mar 17. PMID:18347057^[16]

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

References

↑ Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol. 1997 Apr 1;7(4):261-9. PMID:9094314
↑ Chou MM, Hou W, Johnson J, Graham LK, Lee MH, Chen CS, Newton AC, Schaffhausen BS, Toker A. Regulation of protein kinase C zeta by PI 3-kinase and PDK-1. Curr Biol. 1998 Sep 24;8(19):1069-77. PMID:9768361
↑ Cheng X, Ma Y, Moore M, Hemmings BA, Taylor SS. Phosphorylation and activation of cAMP-dependent protein kinase by phosphoinositide-dependent protein kinase. Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9849-54. PMID:9707564
↑ Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, Thomas G. Phosphorylation and activation of p70s6k by PDK1. Science. 1998 Jan 30;279(5351):707-10. PMID:9445476
↑ Jensen CJ, Buch MB, Krag TO, Hemmings BA, Gammeltoft S, Frodin M. 90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-phosphoinositide-dependent protein kinase-1. J Biol Chem. 1999 Sep 17;274(38):27168-76. PMID:10480933
↑ King CC, Gardiner EM, Zenke FT, Bohl BP, Newton AC, Hemmings BA, Bokoch GM. p21-activated kinase (PAK1) is phosphorylated and activated by 3-phosphoinositide-dependent kinase-1 (PDK1). J Biol Chem. 2000 Dec 29;275(52):41201-9. PMID:10995762 doi:10.1074/jbc.M006553200
↑ Scheid MP, Marignani PA, Woodgett JR. Multiple phosphoinositide 3-kinase-dependent steps in activation of protein kinase B. Mol Cell Biol. 2002 Sep;22(17):6247-60. PMID:12167717
↑ Taniyama Y, Weber DS, Rocic P, Hilenski L, Akers ML, Park J, Hemmings BA, Alexander RW, Griendling KK. Pyk2- and Src-dependent tyrosine phosphorylation of PDK1 regulates focal adhesions. Mol Cell Biol. 2003 Nov;23(22):8019-29. PMID:14585963
↑ Nilsen T, Slagsvold T, Skjerpen CS, Brech A, Stenmark H, Olsnes S. Peroxisomal targeting as a tool for assaying potein-protein interactions in the living cell: cytokine-independent survival kinase (CISK) binds PDK-1 in vivo in a phosphorylation-dependent manner. J Biol Chem. 2004 Feb 6;279(6):4794-801. Epub 2003 Nov 6. PMID:14604990 doi:10.1074/jbc.M309653200
↑ Balendran A, Casamayor A, Deak M, Paterson A, Gaffney P, Currie R, Downes CP, Alessi DR. PDK1 acquires PDK2 activity in the presence of a synthetic peptide derived from the carboxyl terminus of PRK2. Curr Biol. 1999 Apr 22;9(8):393-404. PMID:10226025
↑ Tanaka H, Fujita N, Tsuruo T. 3-Phosphoinositide-dependent protein kinase-1-mediated IkappaB kinase beta (IkkB) phosphorylation activates NF-kappaB signaling. J Biol Chem. 2005 Dec 9;280(49):40965-73. Epub 2005 Oct 5. PMID:16207722 doi:10.1074/jbc.M506235200
↑ Seong HA, Jung H, Choi HS, Kim KT, Ha H. Regulation of transforming growth factor-beta signaling and PDK1 kinase activity by physical interaction between PDK1 and serine-threonine kinase receptor-associated protein. J Biol Chem. 2005 Dec 30;280(52):42897-908. Epub 2005 Oct 26. PMID:16251192 doi:10.1074/jbc.M507539200
↑ Seong HA, Jung H, Kim KT, Ha H. 3-Phosphoinositide-dependent PDK1 negatively regulates transforming growth factor-beta-induced signaling in a kinase-dependent manner through physical interaction with Smad proteins. J Biol Chem. 2007 Apr 20;282(16):12272-89. Epub 2007 Feb 27. PMID:17327236 doi:10.1074/jbc.M609279200
↑ Primo L, di Blasio L, Roca C, Droetto S, Piva R, Schaffhausen B, Bussolino F. Essential role of PDK1 in regulating endothelial cell migration. J Cell Biol. 2007 Mar 26;176(7):1035-47. Epub 2007 Mar 19. PMID:17371830 doi:10.1083/jcb.200607053
↑ Lim WG, Chen X, Liu JP, Tan BJ, Zhou S, Smith A, Lees N, Hou L, Gu F, Yu XY, Du Y, Smith D, Verma C, Liu K, Duan W. The C-terminus of PRK2/PKNgamma is required for optimal activation by RhoA in a GTP-dependent manner. Arch Biochem Biophys. 2008 Nov 15;479(2):170-8. doi: 10.1016/j.abb.2008.09.008., Epub 2008 Sep 22. PMID:18835241 doi:10.1016/j.abb.2008.09.008
↑ Bayascas JR, Wullschleger S, Sakamoto K, Garcia-Martinez JM, Clacher C, Komander D, van Aalten DM, Boini KM, Lang F, Lipina C, Logie L, Sutherland C, Chudek JA, van Diepen JA, Voshol PJ, Lucocq JM, Alessi DR. Mutation of the PDK1 PH domain inhibits protein kinase B/Akt, leading to small size and insulin resistance. Mol Cell Biol. 2008 May;28(10):3258-72. Epub 2008 Mar 17. PMID:18347057 doi:10.1128/MCB.02032-07

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/2vki"

@@ Line 2: / Line 2: @@
 <StructureSection load='2vki' size='340' side='right' caption='[[2vki]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2vki]] is a 1 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=2VKI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2VKI FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2vki]] 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=2VKI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2VKI FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1uu8|1uu8]], [[1oky|1oky]], [[1z5m|1z5m]], [[1uu9|1uu9]], [[1okz|1okz]], [[1w1d|1w1d]], [[1h1w|1h1w]], [[1uu3|1uu3]], [[1w1g|1w1g]], [[2biy|2biy]], [[1w1h|1w1h]], [[1uu7|1uu7]], [[1uvr|1uvr]]</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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2vki FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vki OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2vki RCSB], [http://www.ebi.ac.uk/pdbsum/2vki PDBsum]</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=2vki FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vki OCA], [http://pdbe.org/2vki PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2vki RCSB], [http://www.ebi.ac.uk/pdbsum/2vki PDBsum]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 18: @@
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
-</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
+</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2vki ConSurf].
 <div style="clear:both"></div>
 <div style="background-color:#fffaf0;">
@@ Line 28: / Line 28: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 2vki" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 35: / Line 36: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Non-specific serine/threonine protein kinase]]
 [[Category: Aalten, D M.F Van]]

2vki

From Proteopedia

Revision as of 04:47, 8 February 2016

STRUCTURE OF THE PDK1 PH DOMAIN K465E MUTANT

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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