P53042 (PPP5_RAT) Reviewed, UniProtKB/Swiss-Prot
Last modified February 19, 2014. Version 116. History...
Names and origin
|Protein names||Recommended name:|
Serine/threonine-protein phosphatase 5
Protein phosphatase T
|Organism||Rattus norvegicus (Rat) [Reference proteome]|
|Taxonomic identifier||10116 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus|
|Sequence length||499 AA.|
|Sequence processing||The displayed sequence is further processed into a mature form.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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.2 Ref.3 Ref.4 Ref.5 Ref.6
[a protein]-serine/threonine phosphate + H2O = [a protein]-serine/threonine + phosphate.
Binds 2 divalent metal cation per subutnit By similarity.
Autoinhibited. The TPR domain, unique in that protein family, engage to form an extensive interface with the catalytic region preventig access of the substrate 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. Ref.2 Ref.6
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. Ref.3 Ref.6 Ref.7
Predominantly found in brain and, in lower levels, in testis, but was nearly undetectable in spleen, lung, skeletal muscle, kidney and liver. Ref.4
Proteocally activated by at least two different cleavages which leads to products of 56 and 50 kDa By similarity.
Contains 3 TPR repeats.
KM=12.1 µM for MAPT/TAU (at pH 7.4 and 30 degrees Celsius) Ref.4
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Initiator methionine||1||1||Removed By similarity|
|Chain||2 – 499||498||Serine/threonine-protein phosphatase 5||PRO_0000058897|
|Repeat||28 – 61||34||TPR 1|
|Repeat||62 – 95||34||TPR 2|
|Repeat||96 – 129||34||TPR 3|
|Region||200 – 499||300||Catalytic|
|Region||303 – 304||2||Substrate binding By similarity|
|Region||495 – 499||5||Required for autoinhibition|
|Active site||304||1||Proton donor/acceptor By similarity|
|Metal binding||242||1||Divalent metal cation 1 By similarity|
|Metal binding||244||1||Divalent metal cation 1 By similarity|
|Metal binding||271||1||Divalent metal cation 1 By similarity|
|Metal binding||271||1||Divalent metal cation 2 By similarity|
|Metal binding||303||1||Divalent metal cation 2 By similarity|
|Metal binding||352||1||Divalent metal cation 2 By similarity|
|Metal binding||427||1||Divalent metal cation 2 By similarity|
|Binding site||244||1||Substrate By similarity|
|Binding site||275||1||Substrate By similarity|
|Binding site||400||1||Substrate By similarity|
|Binding site||427||1||Substrate By similarity|
Amino acid modifications
|Modified residue||2||1||N-acetylalanine By similarity|
|Mutagenesis||29||1||E → A: No effect on phosphatase activity. Ref.2|
|Mutagenesis||32||1||K → A: No effect on phosphatase activity. Ref.2|
|Mutagenesis||40||1||K → A: Slightly reduces activation by arachidonic acid.|
|Mutagenesis||56||1||E → A: No effect on phosphatase activity. Ref.2|
|Mutagenesis||63||1||I → A: No effect on phosphatase activity. Ref.2|
|Mutagenesis||74||1||R → A: No effect on phosphatase activity. Ref.2|
|Mutagenesis||76||1||E → A: Increases basal phosphatase activity. Ref.2|
|Mutagenesis||77||1||C → A: No effect on phosphatase activity. Ref.2|
|Mutagenesis||80||1||Y → A: No effect on phosphatase activity. Ref.2|
|Mutagenesis||93||1||K → E: Loss of inhibition of KCNH2 channel stimulation. Ref.6|
|Mutagenesis||97||1||K → A: No effect on phosphatase activity. Ref.2|
|Mutagenesis||101||1||R → A: No effect on phosphatase activity. Ref.2|
|Mutagenesis||126||1||K → A: Loss of inhibition of KCNH2 channel stimulation. Ref.6|
|Mutagenesis||451||1||Y → A: Insensitive to okadaic acid. Ref.6|
|||"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].
|||"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.
|||"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.
|||"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.
|||"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.
|||"Rac GTPase signaling through the PP5 protein phosphatase."|
Gentile S., Darden T., Erxleben C., Romeo C., Russo A., Martin N., Rossie S., Armstrong D.L.
Proc. Natl. Acad. Sci. U.S.A. 103:5202-5206(2006) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN RAC1 SIGNALING, ENZYME REGULATION, INTERACTION WITH RAC1, MUTAGENESIS OF LYS-93; LYS-126 AND TYR-451.
|||"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.
|+||Additional computationally mapped references.|
|X77237 mRNA. Translation: CAA54454.1.|
|RefSeq||NP_113917.1. NM_031729.1. |
3D structure databases
|SMR||P53042. Positions 23-499. |
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSRNOT00000023078; ENSRNOP00000023078; ENSRNOG00000016907. |
|UCSC||RGD:68415. rat. |
|RGD||68415. Ppp5c. |
Enzyme and pathway databases
|BRENDA||220.127.116.11. 5301. |
Gene expression databases
Family and domain databases
|Gene3D||18.104.22.168. 1 hit. |
|InterPro||IPR004843. PEstase_dom. |
|PANTHER||PTHR11668:SF12. PTHR11668:SF12. 1 hit. |
|Pfam||PF00149. Metallophos. 1 hit. |
PF08321. PPP5. 1 hit.
PF00515. TPR_1. 2 hits.
|PIRSF||PIRSF033096. PPPtase_5. 1 hit. |
|PRINTS||PR00114. STPHPHTASE. |
|SMART||SM00156. PP2Ac. 1 hit. |
SM00028. TPR. 3 hits.
|PROSITE||PS00125. SER_THR_PHOSPHATASE. 1 hit. |
PS50005. TPR. 3 hits.
PS50293. TPR_REGION. 1 hit.
|Accession||Primary (citable) accession number: P53042|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|
Index of protein domains and families