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| | ==Rat PP5 co-crystallized with P5SA-2== | | ==Rat PP5 co-crystallized with P5SA-2== |
| - | <StructureSection load='4ja7' size='340' side='right' caption='[[4ja7]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='4ja7' size='340' side='right'caption='[[4ja7]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4ja7]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JA7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4JA7 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4ja7]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JA7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JA7 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 2Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1wao|1wao]], [[4ja9|4ja9]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Ppp5c ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</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=4ja7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ja7 OCA], [https://pdbe.org/4ja7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ja7 RCSB], [https://www.ebi.ac.uk/pdbsum/4ja7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ja7 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/Phosphoprotein_phosphatase Phosphoprotein phosphatase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.3.16 3.1.3.16] </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=4ja7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ja7 OCA], [http://pdbe.org/4ja7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ja7 RCSB], [http://www.ebi.ac.uk/pdbsum/4ja7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ja7 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PPP5_RAT PPP5_RAT]] Serine/threonine-protein phosphatase that dephosphorylates a myriad of proteins involved in different signaling pathways including the kinases CSNK1E, ASK1/MAP3K5, PRKDC and RAF1, the nuclear receptors NR3C1, PPARG, ESR1 and ESR2, SMAD proteins and TAU/MAPT. Implicated in wide ranging cellular processes, including apoptosis, differentiation, DNA damage response, cell survival, regulation of ion channels or circadian rhythms, in response to steroid and thyroid hormones, calcium, fatty acids, TGF-beta as well as oxidative and genotoxic stresses. Participates in the control of DNA damage response mechanisms such as checkpoint activation and DNA damage repair through, for instance, the regulation ATM/ATR-signaling and dephosphorylation of PRKDC and TP53BP1. Inhibits ASK1/MAP3K5-mediated apoptosis induced by oxidative stress. Plays a positive role in adipogenesis, mainly through the dephosphorylation and activation of PPARG transactivation function. Also dephosphorylates and inhibits the anti-adipogenic effect of NR3C1. Regulates the circadian rhythms, through the dephosphorylation and activation of CSNK1E. May modulate TGF-beta signaling pathway by the regulation of SMAD3 phosphorylation and protein expression levels. Dephosphorylates and may play a role in the regulation of TAU/MAPT. Through their dephosphorylation, may play a role in the regulation of ions channels such as KCNH2.<ref>PMID:11523989</ref> <ref>PMID:12176367</ref> <ref>PMID:15546861</ref> <ref>PMID:16892053</ref> <ref>PMID:16549782</ref> | + | [https://www.uniprot.org/uniprot/PPP5_RAT PPP5_RAT] Serine/threonine-protein phosphatase that dephosphorylates a myriad of proteins involved in different signaling pathways including the kinases CSNK1E, ASK1/MAP3K5, PRKDC and RAF1, the nuclear receptors NR3C1, PPARG, ESR1 and ESR2, SMAD proteins and TAU/MAPT. Implicated in wide ranging cellular processes, including apoptosis, differentiation, DNA damage response, cell survival, regulation of ion channels or circadian rhythms, in response to steroid and thyroid hormones, calcium, fatty acids, TGF-beta as well as oxidative and genotoxic stresses. Participates in the control of DNA damage response mechanisms such as checkpoint activation and DNA damage repair through, for instance, the regulation ATM/ATR-signaling and dephosphorylation of PRKDC and TP53BP1. Inhibits ASK1/MAP3K5-mediated apoptosis induced by oxidative stress. Plays a positive role in adipogenesis, mainly through the dephosphorylation and activation of PPARG transactivation function. Also dephosphorylates and inhibits the anti-adipogenic effect of NR3C1. Regulates the circadian rhythms, through the dephosphorylation and activation of CSNK1E. May modulate TGF-beta signaling pathway by the regulation of SMAD3 phosphorylation and protein expression levels. Dephosphorylates and may play a role in the regulation of TAU/MAPT. Through their dephosphorylation, may play a role in the regulation of ions channels such as KCNH2.<ref>PMID:11523989</ref> <ref>PMID:12176367</ref> <ref>PMID:15546861</ref> <ref>PMID:16892053</ref> <ref>PMID:16549782</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Serine/threonine protein phosphatase|Serine/threonine protein phosphatase]] | + | *[[Protein phosphatase 3D structures|Protein phosphatase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Buffalo rat]] | + | [[Category: Large Structures]] |
| - | [[Category: Phosphoprotein phosphatase]] | + | [[Category: Rattus norvegicus]] |
| - | [[Category: Alte, F]] | + | [[Category: Alte F]] |
| - | [[Category: Fischer, G]] | + | [[Category: Fischer G]] |
| - | [[Category: Gemmecker, G]] | + | [[Category: Gemmecker G]] |
| - | [[Category: Groll, M]] | + | [[Category: Groll M]] |
| - | [[Category: Haslbeck, V]] | + | [[Category: Haslbeck V]] |
| - | [[Category: Helmuth, M]] | + | [[Category: Helmuth M]] |
| - | [[Category: Popowicz, G]] | + | [[Category: Popowicz G]] |
| - | [[Category: Richter, K]] | + | [[Category: Richter K]] |
| - | [[Category: Sattler, M]] | + | [[Category: Sattler M]] |
| - | [[Category: Schmidt, W]] | + | [[Category: Schmidt W]] |
| - | [[Category: Striggow, F]] | + | [[Category: Striggow F]] |
| - | [[Category: Weiwad, M]] | + | [[Category: Weiwad M]] |
| - | [[Category: Activation]]
| + | |
| - | [[Category: Hsp90]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Neurodegenerative disease]]
| + | |
| - | [[Category: Pp5]]
| + | |
| - | [[Category: Ser/thr-protein phosphatase domain]]
| + | |
| - | [[Category: Tau-dephosphorylation]]
| + | |
| - | [[Category: Tetratricopeptide repeat domain]]
| + | |
| Structural highlights
Function
PPP5_RAT Serine/threonine-protein phosphatase that dephosphorylates a myriad of proteins involved in different signaling pathways including the kinases CSNK1E, ASK1/MAP3K5, PRKDC and RAF1, the nuclear receptors NR3C1, PPARG, ESR1 and ESR2, SMAD proteins and TAU/MAPT. Implicated in wide ranging cellular processes, including apoptosis, differentiation, DNA damage response, cell survival, regulation of ion channels or circadian rhythms, in response to steroid and thyroid hormones, calcium, fatty acids, TGF-beta as well as oxidative and genotoxic stresses. Participates in the control of DNA damage response mechanisms such as checkpoint activation and DNA damage repair through, for instance, the regulation ATM/ATR-signaling and dephosphorylation of PRKDC and TP53BP1. Inhibits ASK1/MAP3K5-mediated apoptosis induced by oxidative stress. Plays a positive role in adipogenesis, mainly through the dephosphorylation and activation of PPARG transactivation function. Also dephosphorylates and inhibits the anti-adipogenic effect of NR3C1. Regulates the circadian rhythms, through the dephosphorylation and activation of CSNK1E. May modulate TGF-beta signaling pathway by the regulation of SMAD3 phosphorylation and protein expression levels. Dephosphorylates and may play a role in the regulation of TAU/MAPT. Through their dephosphorylation, may play a role in the regulation of ions channels such as KCNH2.[1] [2] [3] [4] [5]
Publication Abstract from PubMed
Protein phosphatase 5 (PP5) is an evolutionary conserved serine/threonine phosphatase. Its dephosphorylation activity modulates a diverse set of cellular factors including protein kinases and the microtubule-associated tau protein involved in neurodegenerative disorders. It is auto-regulated by its heat-shock protein (Hsp90)-interacting tetratricopeptide repeat (TPR) domain and its C-terminal alpha-helix. In the present study, we report the identification of five specific PP5 activators [PP5 small-molecule activators (P5SAs)] that enhance the phosphatase activity up to 8-fold. The compounds are allosteric modulators accelerating efficiently the turnover rate of PP5, but do barely affect substrate binding or the interaction between PP5 and the chaperone Hsp90. Enzymatic studies imply that the compounds bind to the phosphatase domain of PP5. For the most promising compound crystallographic comparisons of the apo PP5 and the PP5-P5SA-2 complex indicate a relaxation of the auto-inhibited state of PP5. Residual electron density and mutation analyses in PP5 suggest activator binding to a pocket in the phosphatase/TPR domain interface, which may exert regulatory functions. These compounds thus may expose regulatory mechanisms in the PP5 enzyme and serve to develop optimized activators based on these scaffolds.
Selective activators of protein phosphatase 5 target the auto-inhibitory mechanism.,Haslbeck V, Drazic A, Eckl JM, Alte F, Helmuth M, Popowicz G, Schmidt W, Braun F, Weiwad M, Fischer G, Gemmecker G, Sattler M, Striggow F, Groll M, Richter K Biosci Rep. 2015 Apr 20;35(3). pii: e00210. doi: 10.1042/BSR20150042. PMID:26182372[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kang H, Sayner SL, Gross KL, Russell LC, Chinkers M. Identification of amino acids in the tetratricopeptide repeat and C-terminal domains of protein phosphatase 5 involved in autoinhibition and lipid activation. Biochemistry. 2001 Sep 4;40(35):10485-90. PMID:11523989
- ↑ Yamaguchi Y, Katoh H, Mori K, Negishi M. Galpha(12) and Galpha(13) interact with Ser/Thr protein phosphatase type 5 and stimulate its phosphatase activity. Curr Biol. 2002 Aug 6;12(15):1353-8. PMID:12176367
- ↑ Liu F, Iqbal K, Grundke-Iqbal I, Rossie S, Gong CX. Dephosphorylation of tau by protein phosphatase 5: impairment in Alzheimer's disease. J Biol Chem. 2005 Jan 21;280(3):1790-6. Epub 2004 Nov 15. PMID:15546861 doi:http://dx.doi.org/10.1074/jbc.M410775200
- ↑ von Kriegsheim A, Pitt A, Grindlay GJ, Kolch W, Dhillon AS. Regulation of the Raf-MEK-ERK pathway by protein phosphatase 5. Nat Cell Biol. 2006 Sep;8(9):1011-6. Epub 2006 Aug 6. PMID:16892053 doi:http://dx.doi.org/10.1038/ncb1465
- ↑ Gentile S, Darden T, Erxleben C, Romeo C, Russo A, Martin N, Rossie S, Armstrong DL. Rac GTPase signaling through the PP5 protein phosphatase. Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):5202-6. Epub 2006 Mar 20. PMID:16549782 doi:http://dx.doi.org/10.1073/pnas.0600080103
- ↑ Haslbeck V, Drazic A, Eckl JM, Alte F, Helmuth M, Popowicz G, Schmidt W, Braun F, Weiwad M, Fischer G, Gemmecker G, Sattler M, Striggow F, Groll M, Richter K. Selective activators of protein phosphatase 5 target the auto-inhibitory mechanism. Biosci Rep. 2015 Apr 20;35(3). pii: e00210. doi: 10.1042/BSR20150042. PMID:26182372 doi:http://dx.doi.org/10.1042/BSR20150042
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