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P53042

- PPP5_RAT

UniProt

P53042 - PPP5_RAT

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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

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. G-protein alpha-subunit binding Source: RGD
  2. heat shock protein binding Source: RGD
  3. metal ion binding Source: UniProtKB-KW
  4. microtubule binding Source: RGD
  5. phosphoprotein phosphatase activity Source: UniProtKB
  6. RNA binding Source: Ensembl
  7. signal transducer activity Source: Ensembl

GO - Biological processi

  1. cellular response to cadmium ion Source: RGD
  2. cellular response to hydrogen peroxide Source: RGD
  3. histone dephosphorylation Source: RGD
  4. negative regulation of cell death Source: RGD
  5. negative regulation of neuron death Source: RGD
  6. negative regulation of protein phosphorylation Source: RGD
  7. positive regulation of glucocorticoid receptor signaling pathway Source: RGD
  8. positive regulation of I-kappaB kinase/NF-kappaB signaling Source: Ensembl
  9. protein dephosphorylation Source: RGD
  10. protein heterooligomerization Source: RGD
  11. protein oligomerization Source: RGD
  12. response to lead ion Source: RGD
  13. response to morphine Source: Ensembl
Complete GO annotation...

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. cell periphery Source: RGD
  2. cytoplasm Source: RGD
  3. cytosol Source: RGD
  4. dendrite Source: RGD
  5. membrane Source: UniProtKB-KW
  6. neuronal cell body Source: RGD
  7. neuron projection Source: RGD
  8. nucleus Source: RGD
  9. perikaryon Source: RGD
Complete GO annotation...

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

ExpressionAtlasiP53042. baseline.
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 – 4017Combined sources
Helixi44 – 5714Combined sources
Helixi62 – 7413Combined sources
Helixi78 – 9114Combined sources
Helixi96 – 10813Combined sources
Helixi112 – 12514Combined sources
Helixi130 – 14819Combined sources
Helixi161 – 1644Combined sources
Helixi167 – 1693Combined sources
Helixi188 – 19912Combined sources
Helixi206 – 22116Combined sources
Beta strandi225 – 2295Combined sources
Beta strandi236 – 2405Combined sources
Helixi247 – 25711Combined sources
Beta strandi262 – 2643Combined sources
Beta strandi266 – 2705Combined sources
Beta strandi273 – 2764Combined sources
Helixi279 – 29214Combined sources
Turni294 – 2963Combined sources
Beta strandi297 – 3004Combined sources
Helixi307 – 3137Combined sources
Helixi315 – 3228Combined sources
Helixi325 – 33511Combined sources
Beta strandi340 – 3445Combined sources
Turni345 – 3473Combined sources
Beta strandi348 – 3536Combined sources
Beta strandi357 – 3593Combined sources
Helixi363 – 3675Combined sources
Beta strandi372 – 3743Combined sources
Beta strandi377 – 3793Combined sources
Helixi380 – 3867Combined sources
Beta strandi391 – 3977Combined sources
Beta strandi401 – 4066Combined sources
Helixi408 – 41811Combined sources
Beta strandi422 – 4254Combined sources
Beta strandi433 – 4375Combined sources
Helixi438 – 4403Combined sources
Beta strandi442 – 4454Combined sources
Helixi451 – 4533Combined sources
Beta strandi459 – 4657Combined sources
Beta strandi468 – 4769Combined sources
Turni486 – 4894Combined sources
Helixi492 – 4943Combined sources

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_dom.
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

        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:
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

ExpressionAtlasi P53042. baseline.
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_dom.
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 29, 2014
This is version 121 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