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P53042

- PPP5_RAT

UniProt

P53042 - PPP5_RAT

Protein

Serine/threonine-protein phosphatase 5

Gene

Ppp5c

Organism
Rattus norvegicus (Rat)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 120 (01 Oct 2014)
      Sequence version 1 (01 Oct 1996)
      Previous versions | rss
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    Functioni

    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 KCNH2.5 Publications

    Catalytic activityi

    [a protein]-serine/threonine phosphate + H2O = [a protein]-serine/threonine + phosphate.1 Publication

    Cofactori

    Binds 2 magnesium or manganese ions per subunit.2 Publications

    Enzyme regulationi

    Autoinhibited. In the autoinhibited state, the TPR domain interacts with the catalytic region and prevents substrate access to the catalytic pocket. Allosterically activated by various polyunsaturated fatty acids, free long-chain fatty-acids and long-chain fatty acyl-CoA esters, arachidonic acid being the most effective activator. HSP90A and probably RAC1, GNA12 and GNA13 can also release the autoinhibition by the TPR repeat. Activation by RAC1, GNA12 and GNA13 is synergistic with the one produced by fatty acids binding. Inhibited by okadaic acid.3 Publications

    Kineticsi

    1. KM=12.1 µM for MAPT/TAU (at pH 7.4 and 30 degrees Celsius)1 Publication

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Metal bindingi242 – 2421Magnesium or manganese 11 Publication
    Metal bindingi244 – 2441Magnesium or manganese 11 Publication
    Binding sitei244 – 2441SubstrateBy similarity
    Metal bindingi271 – 2711Magnesium or manganese 11 Publication
    Metal bindingi271 – 2711Magnesium or manganese 21 Publication
    Binding sitei275 – 2751SubstrateBy similarity
    Metal bindingi303 – 3031Magnesium or manganese 21 Publication
    Active sitei304 – 3041Proton donor/acceptorBy similarity
    Metal bindingi352 – 3521Magnesium or manganese 21 Publication
    Binding sitei400 – 4001SubstrateBy similarity
    Metal bindingi427 – 4271Magnesium or manganese 21 Publication
    Binding sitei427 – 4271SubstrateBy similarity

    GO - Molecular functioni

    1. metal ion binding Source: UniProtKB-KW
    2. phosphoprotein phosphatase activity Source: UniProtKB
    3. RNA binding Source: Ensembl
    4. signal transducer activity Source: Ensembl

    GO - Biological processi

    1. positive regulation of I-kappaB kinase/NF-kappaB signaling Source: Ensembl
    2. protein dephosphorylation Source: InterPro
    3. protein heterooligomerization Source: RGD
    4. response to morphine Source: Ensembl

    Keywords - Molecular functioni

    Hydrolase, Protein phosphatase

    Keywords - Ligandi

    Magnesium, Manganese, Metal-binding

    Enzyme and pathway databases

    BRENDAi3.1.3.16. 5301.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Serine/threonine-protein phosphatase 5 (EC:3.1.3.16)
    Short name:
    PP5
    Alternative name(s):
    Protein phosphatase T
    Short name:
    PPT
    Gene namesi
    Name:Ppp5c
    OrganismiRattus norvegicus (Rat)
    Taxonomic identifieri10116 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeRattus
    ProteomesiUP000002494: Chromosome 1

    Organism-specific databases

    RGDi68415. Ppp5c.

    Subcellular locationi

    Nucleus 1 Publication. Cytoplasm 1 Publication. Membrane By similarity
    Note: Predominantly nuclear. But also present in the cytoplasm.

    GO - Cellular componenti

    1. cytoplasm Source: RGD
    2. cytosol Source: Ensembl
    3. Golgi apparatus Source: Ensembl
    4. membrane Source: UniProtKB-SubCell
    5. neuronal cell body Source: RGD
    6. neuron projection Source: RGD
    7. nucleus Source: RGD

    Keywords - Cellular componenti

    Cytoplasm, Membrane, Nucleus

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi29 – 291E → A: No effect on phosphatase activity. 1 Publication
    Mutagenesisi32 – 321K → A: No effect on phosphatase activity. 1 Publication
    Mutagenesisi40 – 401K → A: Slightly reduces activation by arachidonic acid.
    Mutagenesisi56 – 561E → A: No effect on phosphatase activity. 1 Publication
    Mutagenesisi63 – 631I → A: No effect on phosphatase activity. 1 Publication
    Mutagenesisi74 – 741R → A: No effect on phosphatase activity. 1 Publication
    Mutagenesisi76 – 761E → A: Increases basal phosphatase activity. 1 Publication
    Mutagenesisi77 – 771C → A: No effect on phosphatase activity. 1 Publication
    Mutagenesisi80 – 801Y → A: No effect on phosphatase activity. 1 Publication
    Mutagenesisi93 – 931K → E: Loss of inhibition of KCNH2 channel stimulation. 1 Publication
    Mutagenesisi97 – 971K → A: No effect on phosphatase activity. 1 Publication
    Mutagenesisi101 – 1011R → A: No effect on phosphatase activity. 1 Publication
    Mutagenesisi126 – 1261K → A: Loss of inhibition of KCNH2 channel stimulation. 1 Publication
    Mutagenesisi451 – 4511Y → A: Insensitive to okadaic acid. 1 Publication

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Initiator methioninei1 – 11RemovedBy similarity
    Chaini2 – 499498Serine/threonine-protein phosphatase 5PRO_0000058897Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Modified residuei2 – 21N-acetylalanineBy similarity

    Post-translational modificationi

    Activated by at least two different proteolytic cleavages producing a 56 kDa and a 50 kDa form.By similarity

    Keywords - PTMi

    Acetylation

    Proteomic databases

    PRIDEiP53042.

    Expressioni

    Tissue specificityi

    Predominantly found in brain and, in lower levels, in testis, but was nearly undetectable in spleen, lung, skeletal muscle, kidney and liver.1 Publication

    Gene expression databases

    ArrayExpressiP53042.
    GenevestigatoriP53042.

    Interactioni

    Subunit structurei

    Part of a complex with HSP90/HSP90AA1 and steroid receptors. Interacts with CDC16, CDC27. Interacts with KLHDC10 (via the 6 Kelch repeats); inhibits the phosphatase activity on MAP3K5. Interacts (via TPR repeats) with HSP90AA1 (via TPR repeat-binding motif) or HSPA1A/HSPA1B; the interaction is direct and activates the phosphatase activity. Dissociates from HSPA1A/HSPA1B and HSP90AA1 in response to arachidonic acid. Interacts with ATM and ATR; both interactions are induced by DNA damage and enhance ATM and ATR kinase activity. Interacts with RAD17; reduced by DNA damage. Interacts with nuclear receptors such as NR3C1/GCR and PPARG (activated by agonist); regulates their transactivation activities. Interacts (via TPR repeats) with S100 proteins S100A1, S100A2, S100A6, S100B and S100P; the interactions are calcium-dependent, strongly activate PPP5C phosphatase activity and compete with HSP90AA1 and MAP3K5 interactions. Interacts with SMAD2 and SMAD3 but not with SMAD1; decreases SMAD3 phosphorylation and protein levels. Interacts (via TPR repeats) with CRY1 and CRY2; the interaction with CRY2 downregulates the phosphatase activity on CSNK1E. Interacts (via TPR repeats) with the active form of RAC1, GNA12 or GNA13; these interactions activate the phosphatase activity and translocate PPP5C to the cell membrane.4 Publications

    Structurei

    Secondary structure

    1
    499
    Legend: HelixTurnBeta strand
    Show more details
    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Helixi24 – 4017
    Helixi44 – 5714
    Helixi62 – 7413
    Helixi78 – 9114
    Helixi96 – 10813
    Helixi112 – 12514
    Helixi130 – 14819
    Helixi161 – 1644
    Helixi167 – 1693
    Helixi188 – 19912
    Helixi206 – 22116
    Beta strandi225 – 2295
    Beta strandi236 – 2405
    Helixi247 – 25711
    Beta strandi262 – 2643
    Beta strandi266 – 2705
    Beta strandi273 – 2764
    Helixi279 – 29214
    Turni294 – 2963
    Beta strandi297 – 3004
    Helixi307 – 3137
    Helixi315 – 3228
    Helixi325 – 33511
    Beta strandi340 – 3445
    Turni345 – 3473
    Beta strandi348 – 3536
    Beta strandi357 – 3593
    Helixi363 – 3675
    Beta strandi372 – 3743
    Beta strandi377 – 3793
    Helixi380 – 3867
    Beta strandi391 – 3977
    Beta strandi401 – 4066
    Helixi408 – 41811
    Beta strandi422 – 4254
    Beta strandi433 – 4375
    Helixi438 – 4403
    Beta strandi442 – 4454
    Helixi451 – 4533
    Beta strandi459 – 4657
    Beta strandi468 – 4769
    Turni486 – 4894
    Helixi492 – 4943

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    EntryMethodResolution (Å)ChainPositionsPDBsum
    4JA7X-ray2.00A16-499[»]
    4JA9X-ray2.30A16-499[»]
    ProteinModelPortaliP53042.
    SMRiP53042. Positions 23-499.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Repeati28 – 6134TPR 1Add
    BLAST
    Repeati62 – 9534TPR 2Add
    BLAST
    Repeati96 – 12934TPR 3Add
    BLAST

    Region

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Regioni200 – 499300CatalyticAdd
    BLAST
    Regioni303 – 3042Substrate bindingBy similarity
    Regioni495 – 4995Required for autoinhibition

    Sequence similaritiesi

    Contains 3 TPR repeats.PROSITE-ProRule annotation

    Keywords - Domaini

    Repeat, TPR repeat

    Phylogenomic databases

    eggNOGiCOG0639.
    GeneTreeiENSGT00530000063173.
    HOGENOMiHOG000172698.
    HOVERGENiHBG000216.
    InParanoidiP53042.
    KOiK04460.
    OMAiFKLLYPN.
    OrthoDBiEOG7V49Z3.
    PhylomeDBiP53042.
    TreeFamiTF105562.

    Family and domain databases

    Gene3Di1.25.40.10. 1 hit.
    3.60.21.10. 1 hit.
    InterProiIPR004843. Calcineurin-like_PHP_apaH.
    IPR029052. Metallo-depent_PP-like.
    IPR013235. PPP_dom.
    IPR006186. Ser/Thr-sp_prot-phosphatase.
    IPR011236. Ser/Thr_PPase_5.
    IPR013026. TPR-contain_dom.
    IPR011990. TPR-like_helical.
    IPR001440. TPR_1.
    IPR019734. TPR_repeat.
    [Graphical view]
    PANTHERiPTHR11668:SF12. PTHR11668:SF12. 1 hit.
    PfamiPF00149. Metallophos. 1 hit.
    PF08321. PPP5. 1 hit.
    PF00515. TPR_1. 2 hits.
    [Graphical view]
    PIRSFiPIRSF033096. PPPtase_5. 1 hit.
    PRINTSiPR00114. STPHPHTASE.
    SMARTiSM00156. PP2Ac. 1 hit.
    SM00028. TPR. 3 hits.
    [Graphical view]
    SUPFAMiSSF56300. SSF56300. 1 hit.
    PROSITEiPS00125. SER_THR_PHOSPHATASE. 1 hit.
    PS50005. TPR. 3 hits.
    PS50293. TPR_REGION. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    P53042-1 [UniParc]FASTAAdd to Basket

    « Hide

    MAMAEGERTE CAEPPRDEPP AEGTLKRAEE LKTQANDYFK AKDYENAIKF    50
    YSQAIELNPS NAIYYGNRSL AYLRTECYGY ALGDATRAIE LDKKYIKGYY 100
    RRAASNMALG KFRAALRDYE TVVKVKPNDK DAKMKYQECS KIVKQKAFER 150
    AIAGDEHRRS VVDSLDIESM TIEDEYSGPK LEDGKVTITF MKDLMQWYKD 200
    QKKLHRKCAY QILVQVKEVL CKLSTLVETT LKETEKITVC GDTHGQFYDL 250
    LNIFELNGLP SETNPYIFNG DFVDRGSFSV EVILTLFGFK LLYPDHFHLL 300
    RGNHETDNMN QIYGFEGEVK AKYTAQMYEL FSEVFEWLPL AQCINGKVLI 350
    MHGGLFSEDG VTLDDIRKIE RNRQPPDSGP MCDLLWSDPQ PQNGRSVSKR 400
    GVSCQFGPDV TKAFLEENQL DYIIRSHEVK AEGYEVAHGG RCVTVFSAPN 450
    YCDQMGNKAS YIHLQGSDLR PQFHQFTAVP HPNVKPMAYA NTLLQLGMM 499
    Length:499
    Mass (Da):56,917
    Last modified:October 1, 1996 - v1
    Checksum:i720A7FB7AFC701D2
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    X77237 mRNA. Translation: CAA54454.1.
    PIRiA55346.
    RefSeqiNP_113917.1. NM_031729.1.
    UniGeneiRn.6107.

    Genome annotation databases

    EnsembliENSRNOT00000023078; ENSRNOP00000023078; ENSRNOG00000016907.
    GeneIDi65179.
    KEGGirno:65179.
    UCSCiRGD:68415. rat.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    X77237 mRNA. Translation: CAA54454.1 .
    PIRi A55346.
    RefSeqi NP_113917.1. NM_031729.1.
    UniGenei Rn.6107.

    3D structure databases

    Select the link destinations:
    PDBe
    RCSB PDB
    PDBj
    Links Updated
    Entry Method Resolution (Å) Chain Positions PDBsum
    4JA7 X-ray 2.00 A 16-499 [» ]
    4JA9 X-ray 2.30 A 16-499 [» ]
    ProteinModelPortali P53042.
    SMRi P53042. Positions 23-499.
    ModBasei Search...
    MobiDBi Search...

    Proteomic databases

    PRIDEi P53042.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSRNOT00000023078 ; ENSRNOP00000023078 ; ENSRNOG00000016907 .
    GeneIDi 65179.
    KEGGi rno:65179.
    UCSCi RGD:68415. rat.

    Organism-specific databases

    CTDi 5536.
    RGDi 68415. Ppp5c.

    Phylogenomic databases

    eggNOGi COG0639.
    GeneTreei ENSGT00530000063173.
    HOGENOMi HOG000172698.
    HOVERGENi HBG000216.
    InParanoidi P53042.
    KOi K04460.
    OMAi FKLLYPN.
    OrthoDBi EOG7V49Z3.
    PhylomeDBi P53042.
    TreeFami TF105562.

    Enzyme and pathway databases

    BRENDAi 3.1.3.16. 5301.

    Miscellaneous databases

    NextBioi 614076.
    PROi P53042.

    Gene expression databases

    ArrayExpressi P53042.
    Genevestigatori P53042.

    Family and domain databases

    Gene3Di 1.25.40.10. 1 hit.
    3.60.21.10. 1 hit.
    InterProi IPR004843. Calcineurin-like_PHP_apaH.
    IPR029052. Metallo-depent_PP-like.
    IPR013235. PPP_dom.
    IPR006186. Ser/Thr-sp_prot-phosphatase.
    IPR011236. Ser/Thr_PPase_5.
    IPR013026. TPR-contain_dom.
    IPR011990. TPR-like_helical.
    IPR001440. TPR_1.
    IPR019734. TPR_repeat.
    [Graphical view ]
    PANTHERi PTHR11668:SF12. PTHR11668:SF12. 1 hit.
    Pfami PF00149. Metallophos. 1 hit.
    PF08321. PPP5. 1 hit.
    PF00515. TPR_1. 2 hits.
    [Graphical view ]
    PIRSFi PIRSF033096. PPPtase_5. 1 hit.
    PRINTSi PR00114. STPHPHTASE.
    SMARTi SM00156. PP2Ac. 1 hit.
    SM00028. TPR. 3 hits.
    [Graphical view ]
    SUPFAMi SSF56300. SSF56300. 1 hit.
    PROSITEi PS00125. SER_THR_PHOSPHATASE. 1 hit.
    PS50005. TPR. 3 hits.
    PS50293. TPR_REGION. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "Molecular cloning of a protein serine/threonine phosphatase containing a putative regulatory tetratricopeptide repeat domain."
      Becker W., Kentrup H., Klumpp S., Schultz J.E., Joost H.G.
      J. Biol. Chem. 269:22586-22592(1994) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA].
      Strain: Sprague-Dawley.
      Tissue: Testis.
    2. "Identification of amino acids in the tetratricopeptide repeat and C-terminal domains of protein phosphatase 5 involved in autoinhibition and lipid activation."
      Kang H., Sayner S.L., Gross K.L., Russell L.C., Chinkers M.
      Biochemistry 40:10485-10490(2001) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION AS PHOSPHATASE, ENZYME REGULATION, MUTAGENESIS OF GLU-29; LYS-32; GLU-56; ILE-63; ARG-74; GLU-76; CYS-77; TYR-80; LYS-97 AND ARG-101.
    3. "Identification of potential physiological activators of protein phosphatase 5."
      Ramsey A.J., Chinkers M.
      Biochemistry 41:5625-5632(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: COFACTOR, ENZYME REGULATION, CATALYTIC ACTIVITY.
    4. "Galpha(12) and Galpha(13) interact with Ser/Thr protein phosphatase type 5 and stimulate its phosphatase activity."
      Yamaguchi Y., Katoh H., Mori K., Negishi M.
      Curr. Biol. 12:1353-1358(2002) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION AS PHOSPHATASE, INTERACTION WITH GNA12 AND GNA13, SUBCELLULAR LOCATION.
    5. "Dephosphorylation of tau by protein phosphatase 5: impairment in Alzheimer's disease."
      Liu F., Iqbal K., Grundke-Iqbal I., Rossie S., Gong C.X.
      J. Biol. Chem. 280:1790-1796(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN DEPHOSPHORYLATING MAPT, BIOPHYSICOCHEMICAL PROPERTIES, TISSUE SPECIFICITY.
    6. "Regulation of the Raf-MEK-ERK pathway by protein phosphatase 5."
      von Kriegsheim A., Pitt A., Grindlay G.J., Kolch W., Dhillon A.S.
      Nat. Cell Biol. 8:1011-1016(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN MAPK SIGNALING.
    7. Cited for: FUNCTION IN RAC1 SIGNALING, ENZYME REGULATION, INTERACTION WITH RAC1, MUTAGENESIS OF LYS-93; LYS-126 AND TYR-451.
    8. "Posttranslational regulation of the mammalian circadian clock by cryptochrome and protein phosphatase 5."
      Partch C.L., Shields K.F., Thompson C.L., Selby C.P., Sancar A.
      Proc. Natl. Acad. Sci. U.S.A. 103:10467-10472(2006) [PubMed] [Europe PMC] [Abstract]
      Cited for: INTERACTION WITH CRY1 AND CRY2.
    9. "Selective targeting of the autoinhibition of PP5 reduces tau phosphorylation in mouse."
      Haslbeck V., Helmuth M., Alte F., Popowicz G., Schmidt W., Weiwad M., Fischer G., Gemmecker G., Sattler M., Striggow F., Groll M., Richter K.
      Submitted (FEB-2013) to the PDB data bank
      Cited for: X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 16-499 IN COMPLEX WITH MAGNESIUM, COFACTOR.

    Entry informationi

    Entry nameiPPP5_RAT
    AccessioniPrimary (citable) accession number: P53042
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: October 1, 1996
    Last sequence update: October 1, 1996
    Last modified: October 1, 2014
    This is version 120 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    2. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3