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Protein

Serine/threonine-protein phosphatase 5

Gene

Ppp5c

Organism
Rattus norvegicus (Rat)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

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

Mg2+2 Publications, Mn2+2 PublicationsNote: 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)DescriptionActionsGraphical viewLength
    Metal bindingi242Magnesium 1Combined sources1 Publication1
    Metal bindingi244Magnesium 1; via tele nitrogenCombined sources1 Publication1
    Binding sitei244SubstrateBy similarity1
    Metal bindingi271Magnesium 1Combined sources1 Publication1
    Metal bindingi271Magnesium 2Combined sources1 Publication1
    Binding sitei275SubstrateBy similarity1
    Metal bindingi303Magnesium 2Combined sources1 Publication1
    Active sitei304Proton donor/acceptorBy similarity1
    Metal bindingi352Magnesium 2; via tele nitrogenCombined sources1 Publication1
    Binding sitei400SubstrateBy similarity1
    Metal bindingi427Magnesium 2; via pros nitrogenCombined sources1 Publication1
    Binding sitei427SubstrateBy similarity1

    GO - Molecular functioni

    • ADP binding Source: RGD
    • ATP binding Source: RGD
    • G-protein alpha-subunit binding Source: RGD
    • heat shock protein binding Source: RGD
    • Hsp90 protein binding Source: RGD
    • identical protein binding Source: RGD
    • metal ion binding Source: UniProtKB-KW
    • microtubule binding Source: RGD
    • phosphoprotein phosphatase activity Source: UniProtKB
    • protein serine/threonine phosphatase activity Source: ARUK-UCL
    • RNA binding Source: RGD
    • signal transducer activity Source: RGD

    GO - Biological processi

    • cellular response to cadmium ion Source: RGD
    • cellular response to hydrogen peroxide Source: RGD
    • histone dephosphorylation Source: RGD
    • negative regulation of cell death Source: RGD
    • negative regulation of neuron death Source: RGD
    • negative regulation of protein phosphorylation Source: RGD
    • positive regulation of glucocorticoid receptor signaling pathway Source: RGD
    • positive regulation of I-kappaB kinase/NF-kappaB signaling Source: RGD
    • protein dephosphorylation Source: RGD
    • protein heterooligomerization Source: RGD
    • protein oligomerization Source: RGD
    • response to arachidonic acid Source: ARUK-UCL
    • response to lead ion Source: ARUK-UCL
    • response to morphine Source: RGD

    Keywordsi

    Molecular functionHydrolase, Protein phosphatase
    LigandMagnesium, Manganese, Metal-binding

    Enzyme and pathway databases

    BRENDAi3.1.3.16 5301
    ReactomeiR-RNO-5675221 Negative regulation of MAPK pathway
    R-RNO-5693565 Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks
    SABIO-RKiP53042

    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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeRattus
    Proteomesi
    • UP000002494 Componenti: Chromosome 1

    Organism-specific databases

    RGDi68415 Ppp5c

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Keywords - Cellular componenti

    Cell membrane, Cytoplasm, Membrane, Nucleus

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi29E → A: No effect on phosphatase activity. 1 Publication1
    Mutagenesisi32K → A: No effect on phosphatase activity. 1 Publication1
    Mutagenesisi40K → A: Slightly reduces activation by arachidonic acid. 1
    Mutagenesisi56E → A: No effect on phosphatase activity. 1 Publication1
    Mutagenesisi63I → A: No effect on phosphatase activity. 1 Publication1
    Mutagenesisi74R → A: No effect on phosphatase activity. 1 Publication1
    Mutagenesisi76E → A: Increases basal phosphatase activity. 1 Publication1
    Mutagenesisi77C → A: No effect on phosphatase activity. 1 Publication1
    Mutagenesisi80Y → A: No effect on phosphatase activity. 1 Publication1
    Mutagenesisi93K → E: Loss of inhibition of KCNH2 channel stimulation. 1 Publication1
    Mutagenesisi97K → A: No effect on phosphatase activity. 1 Publication1
    Mutagenesisi101R → A: No effect on phosphatase activity. 1 Publication1
    Mutagenesisi126K → A: Loss of inhibition of KCNH2 channel stimulation. 1 Publication1
    Mutagenesisi451Y → A: Insensitive to okadaic acid. 1 Publication1

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Initiator methionineiRemovedBy similarity
    ChainiPRO_00000588972 – 499Serine/threonine-protein phosphatase 5Add BLAST498

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei2N-acetylalanineBy similarity1

    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

    PaxDbiP53042
    PRIDEiP53042

    PTM databases

    iPTMnetiP53042
    PhosphoSitePlusiP53042
    SwissPalmiP53042

    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

    BgeeiENSRNOG00000016907
    GenevisibleiP53042 RN

    Interactioni

    Subunit structurei

    Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2 (By similarity). Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 (By similarity). Part of a complex with HSP90/HSP90AA1 and steroid receptors (By similarity). Interacts (via TPR repeats) with HSP90AA1 (via TPR repeat-binding motif) or HSPA1A/HSPA1B; the interaction is direct and activates the phosphatase activity (PubMed:26182372). Dissociates from HSPA1A/HSPA1B and HSP90AA1 in response to arachidonic acid (By similarity). Interacts with CPNE1 (via VWFA domain) (By similarity). Interacts with CDC16, CDC27 (By similarity). Interacts with KLHDC10 (via the 6 Kelch repeats); inhibits the phosphatase activity on MAP3K5 (By similarity). Interacts with ATM and ATR; both interactions are induced by DNA damage and enhance ATM and ATR kinase activity (By similarity). Interacts with RAD17; reduced by DNA damage (By similarity). Interacts with nuclear receptors such as NR3C1/GCR and PPARG (activated by agonist); regulates their transactivation activities (By similarity). 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 (By similarity). Interacts with SMAD2 and SMAD3 but not with SMAD1; decreases SMAD3 phosphorylation and protein levels (By similarity). Interacts (via TPR repeats) with CRY1 and CRY2; the interaction with CRY2 downregulates the phosphatase activity on CSNK1E (PubMed:16790549). 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 (PubMed:12176367, PubMed:16549782). Interacts with FLCN (By similarity).By similarity4 Publications

    GO - Molecular functioni

    • G-protein alpha-subunit binding Source: RGD
    • heat shock protein binding Source: RGD
    • Hsp90 protein binding Source: RGD
    • identical protein binding Source: RGD
    • microtubule binding Source: RGD

    Protein-protein interaction databases

    DIPiDIP-61212N
    IntActiP53042, 2 interactors
    STRINGi10116.ENSRNOP00000023078

    Structurei

    Secondary structure

    1499
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Helixi24 – 40Combined sources17
    Helixi44 – 57Combined sources14
    Helixi62 – 74Combined sources13
    Helixi78 – 91Combined sources14
    Helixi96 – 108Combined sources13
    Helixi112 – 125Combined sources14
    Helixi130 – 148Combined sources19
    Helixi161 – 164Combined sources4
    Helixi167 – 169Combined sources3
    Helixi188 – 199Combined sources12
    Helixi206 – 221Combined sources16
    Beta strandi225 – 229Combined sources5
    Beta strandi236 – 240Combined sources5
    Helixi247 – 257Combined sources11
    Beta strandi262 – 264Combined sources3
    Beta strandi266 – 270Combined sources5
    Beta strandi273 – 276Combined sources4
    Helixi279 – 292Combined sources14
    Turni294 – 296Combined sources3
    Beta strandi297 – 300Combined sources4
    Helixi307 – 313Combined sources7
    Helixi315 – 322Combined sources8
    Helixi325 – 335Combined sources11
    Beta strandi340 – 344Combined sources5
    Turni345 – 347Combined sources3
    Beta strandi348 – 353Combined sources6
    Beta strandi357 – 359Combined sources3
    Helixi363 – 367Combined sources5
    Beta strandi372 – 374Combined sources3
    Beta strandi377 – 379Combined sources3
    Helixi380 – 386Combined sources7
    Beta strandi391 – 397Combined sources7
    Beta strandi401 – 406Combined sources6
    Helixi408 – 418Combined sources11
    Beta strandi422 – 425Combined sources4
    Beta strandi433 – 437Combined sources5
    Helixi438 – 440Combined sources3
    Beta strandi442 – 445Combined sources4
    Helixi451 – 453Combined sources3
    Beta strandi459 – 465Combined sources7
    Beta strandi468 – 476Combined sources9
    Turni486 – 489Combined sources4
    Helixi492 – 494Combined sources3

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    4JA7X-ray2.00A16-499[»]
    4JA9X-ray2.30A16-499[»]
    ProteinModelPortaliP53042
    SMRiP53042
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Repeati28 – 61TPR 1Add BLAST34
    Repeati62 – 95TPR 2Add BLAST34
    Repeati96 – 129TPR 3Add BLAST34

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni200 – 499CatalyticAdd BLAST300
    Regioni303 – 304Substrate bindingBy similarity2
    Regioni495 – 499Required for autoinhibition1 Publication5

    Sequence similaritiesi

    Keywords - Domaini

    Repeat, TPR repeat

    Phylogenomic databases

    eggNOGiKOG0376 Eukaryota
    COG0639 LUCA
    GeneTreeiENSGT00530000063173
    HOGENOMiHOG000172698
    HOVERGENiHBG000216
    InParanoidiP53042
    KOiK04460
    OMAiLYPNHFF
    OrthoDBiEOG091G0589
    PhylomeDBiP53042
    TreeFamiTF105562

    Family and domain databases

    Gene3Di1.25.40.10, 1 hit
    3.60.21.10, 1 hit
    InterProiView protein in InterPro
    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_dom_sf
    IPR001440 TPR_1
    IPR019734 TPR_repeat
    PANTHERiPTHR11668:SF391 PTHR11668:SF391, 1 hit
    PfamiView protein in Pfam
    PF00149 Metallophos, 1 hit
    PF08321 PPP5, 1 hit
    PF00515 TPR_1, 1 hit
    PRINTSiPR00114 STPHPHTASE
    SMARTiView protein in SMART
    SM00156 PP2Ac, 1 hit
    SM00028 TPR, 3 hits
    SUPFAMiSSF48452 SSF48452, 1 hit
    PROSITEiView protein in PROSITE
    PS00125 SER_THR_PHOSPHATASE, 1 hit
    PS50005 TPR, 3 hits
    PS50293 TPR_REGION, 1 hit

    Sequencei

    Sequence statusi: Complete.

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

    P53042-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MAMAEGERTE CAEPPRDEPP AEGTLKRAEE LKTQANDYFK AKDYENAIKF
    60 70 80 90 100
    YSQAIELNPS NAIYYGNRSL AYLRTECYGY ALGDATRAIE LDKKYIKGYY
    110 120 130 140 150
    RRAASNMALG KFRAALRDYE TVVKVKPNDK DAKMKYQECS KIVKQKAFER
    160 170 180 190 200
    AIAGDEHRRS VVDSLDIESM TIEDEYSGPK LEDGKVTITF MKDLMQWYKD
    210 220 230 240 250
    QKKLHRKCAY QILVQVKEVL CKLSTLVETT LKETEKITVC GDTHGQFYDL
    260 270 280 290 300
    LNIFELNGLP SETNPYIFNG DFVDRGSFSV EVILTLFGFK LLYPDHFHLL
    310 320 330 340 350
    RGNHETDNMN QIYGFEGEVK AKYTAQMYEL FSEVFEWLPL AQCINGKVLI
    360 370 380 390 400
    MHGGLFSEDG VTLDDIRKIE RNRQPPDSGP MCDLLWSDPQ PQNGRSVSKR
    410 420 430 440 450
    GVSCQFGPDV TKAFLEENQL DYIIRSHEVK AEGYEVAHGG RCVTVFSAPN
    460 470 480 490
    YCDQMGNKAS YIHLQGSDLR PQFHQFTAVP HPNVKPMAYA NTLLQLGMM
    Length:499
    Mass (Da):56,917
    Last modified:October 1, 1996 - v1
    Checksum:i720A7FB7AFC701D2
    GO

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    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

    Similar proteinsi

    Entry informationi

    Entry nameiPPP5_RAT
    AccessioniPrimary (citable) accession number: P53042
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1996
    Last sequence update: October 1, 1996
    Last modified: April 25, 2018
    This is version 152 of the entry and version 1 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome
    UniProt is an ELIXIR core data resource
    Main funding by: National Institutes of Health