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Signaling protein,hydrolase PDB id
2ie4
Jmol
Contents
Protein chains
581 a.a. *
288 a.a. *
Ligands
OKA
Metals
_MN ×2
Waters ×64
* Residue conservation analysis
PDB id:
2ie4
Name: Signaling protein,hydrolase
Title: Structure of the protein phosphatase 2a core enzyme bound to okadaic acid
Structure: Protein phosphatase 2, regulatory subunit a (pr 65), alpha isoform. Chain: a. Fragment: scaffolding subunit. Synonym: protein phosphatase 2a. Engineered: yes. Serine/threonine-protein phosphatase 2a catalytic subunit alpha isoform. Chain: c.
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ppp2r1a. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Gene: ppp2ca. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.
Biol. unit: Tetramer (from PQS)
Resolution:
2.60Å     R-factor:   0.270     R-free:   0.230
Authors: Y.Xing,Y.Xu,Y.Chen,P.D.Jeffrey,Y.Chao,Y.Shi
Key ref:
Y.Xing et al. (2006). Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins. Cell, 127, 341-353. PubMed id: 17055435 DOI: 10.1016/j.cell.2006.09.025
Date:
17-Sep-06     Release date:   07-Nov-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P30153  (2AAA_HUMAN) -  Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform
Seq:
Struc: 		 
Seq:
Struc: 		589 a.a.
581 a.a.
Protein chain
Pfam   ArchSchema ?
P67775  (PP2AA_HUMAN) -  Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
Seq:
Struc: 		309 a.a.
288 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: Chain C: E.C.3.1.3.16  - Phosphoprotein phosphatase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: A phosphoprotein + H2O = a protein + phosphate
phosphoprotein
 + H(2)O
 = protein
 + phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   13 terms 
  Biological process     positive regulation of protein serine/threonine kinase activity   32 terms 
  Biochemical function     binding     11 terms  

 

 
    Added reference    
 
 
DOI no: 10.1016/j.cell.2006.09.025 Cell 127:341-353 (2006)
PubMed id: 17055435  
 
 
Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins.
Y.Xing, Y.Xu, Y.Chen, P.D.Jeffrey, Y.Chao, Z.Lin, Z.Li, S.Strack, J.B.Stock, Y.Shi.
 
  ABSTRACT  
 
The serine/threonine phosphatase protein phosphatase 2A (PP2A) plays an essential role in many aspects of cellular functions and has been shown to be an important tumor suppressor. The core enzyme of PP2A comprises a 65 kDa scaffolding subunit and a 36 kDa catalytic subunit. Here we report the crystal structures of the PP2A core enzyme bound to two of its inhibitors, the tumor-inducing agents okadaic acid and microcystin-LR, at 2.6 and 2.8 A resolution, respectively. The catalytic subunit recognizes one end of the elongated scaffolding subunit by interacting with the conserved ridges of HEAT repeats 11-15. Formation of the core enzyme forces the scaffolding subunit to undergo pronounced structural rearrangement. The scaffolding subunit exhibits considerable conformational flexibility, which is proposed to play an essential role in PP2A function. These structures, together with biochemical analyses, reveal significant insights into PP2A function and serve as a framework for deciphering the diverse roles of PP2A in cellular physiology.
 
  Selected figure(s)  
 
Figure 3.
Figure 3. Specific Interactions between the Scaffolding Subunit and the Catalytic Subunit 		Figure 5.
Figure 5. Conformational Flexibility of the Scaffolding Subunit
 
  The above figures are reprinted by permission from Cell Press: Cell (2006, 127, 341-353) copyright 2006.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21240543 M.B.Karmacharya, and J.W.Soh (2011).
Bioinformatic identification of novel protein phosphatases in the dog genome.
  Mol Cell Biochem, 351, 149-156.  
20875039 S.J.Norwood, D.J.Shaw, N.P.Cowieson, D.J.Owen, R.D.Teasdale, and B.M.Collins (2011).
Assembly and solution structure of the core retromer protein complex.
  Traffic, 12, 56-71.
PDB codes: 3lh8 3lh9 3lha
21288162 S.R.Pereira, V.T.Vasconcelos, and A.Antunes (2011).
The phosphoprotein phosphatase family of Ser/Thr phosphatases as principal targets of naturally occurring toxins.
  Crit Rev Toxicol, 41, 83.  
21080067 T.D.Foley, S.L.Melideo, A.E.Healey, E.J.Lucas, and J.A.Koval (2011).
Phenylarsine oxide binding reveals redox-active and potential regulatory vicinal thiols on the catalytic subunit of protein phosphatase 2A.
  Neurochem Res, 36, 232-240.  
21292165 V.Stanevich, L.Jiang, K.A.Satyshur, Y.Li, P.D.Jeffrey, Z.Li, P.Menden, M.F.Semmelhack, and Y.Xing (2011).
The structural basis for tight control of PP2A methylation and function by LCMT-1.
  Mol Cell, 41, 331-342.
PDB code: 3p71
20162015 A.Campos, and V.Vasconcelos (2010).
Molecular mechanisms of microcystin toxicity in animal cells.
  Int J Mol Sci, 11, 268-287.  
19699225 F.Guo, T.An, and K.S.Rein (2010).
The algal hepatoxoxin okadaic acid is a substrate for human cytochromes CYP3A4 and CYP3A5.
  Toxicon, 55, 325-332.  
20411119 I.Sainis, D.Fokas, K.Vareli, A.G.Tzakos, V.Kounnis, and E.Briasoulis (2010).
Cyanobacterial cyclopeptides as lead compounds to novel targeted cancer drugs.
  Mar Drugs, 8, 629-657.  
21187329 K.Zeng, R.N.Bastos, F.A.Barr, and U.Gruneberg (2010).
Protein phosphatase 6 regulates mitotic spindle formation by controlling the T-loop phosphorylation state of Aurora A bound to its activator TPX2.
  J Cell Biol, 191, 1315-1332.  
20186153 L.Xiao, L.L.Gong, D.Yuan, M.Deng, X.M.Zeng, L.L.Chen, L.Zhang, Q.Yan, J.P.Liu, X.H.Hu, S.M.Sun, J.Liu, H.L.Ma, C.B.Zheng, H.Fu, P.C.Chen, J.Q.Zhao, S.S.Xie, L.J.Zou, Y.M.Xiao, W.B.Liu, J.Zhang, Y.Liu, and D.W.Li (2010).
Protein phosphatase-1 regulates Akt1 signal transduction pathway to control gene expression, cell survival and differentiation.
  Cell Death Differ, 17, 1448-1462.  
20446082 V.Fessard, and L.Le Hégarat (2010).
A strategy to study genotoxicity: application to aquatic toxins, limits and solutions.
  Anal Bioanal Chem, 397, 1715-1722.  
19727590 H.Fu, H.Ma, C.Zheng, J.Lü, X.Yu, C.Li, Y.Peng, G.Liao, W.Liu, Y.Xiao, Y.Liu, and D.W.Li (2009).
Molecular cloning and differential expression patterns of the regulatory subunit B' gene of PP2A in goldfish, Carassius auratus.
  Sci China C Life Sci, 52, 724-732.  
19750005 H.G.Chen, W.J.Han, M.Deng, J.Qin, D.Yuan, J.P.Liu, L.Xiao, L.Gong, S.Liang, J.Zhang, Y.Liu, and D.W.Li (2009).
Transcriptional regulation of PP2A-A alpha is mediated by multiple factors including AP-2alpha, CREB, ETS-1, and SP-1.
  PLoS One, 4, e7019.  
19835610 J.Guergnon, U.Derewenda, J.R.Edelson, and D.L.Brautigan (2009).
Mapping of protein phosphatase-6 association with its SAPS domain regulatory subunit using a model of helical repeats.
  BMC Biochem, 10, 24.  
19657535 K.Vareli, G.Pilidis, M.C.Mavrogiorgou, E.Briasoulis, and I.Sainis (2009).
Molecular characterization of cyanobacterial diversity and yearly fluctuations of Microcystin loads in a suburban Mediterranean Lake (Lake Pamvotis, Greece).
  J Environ Monit, 11, 1506-1512.  
18782753 M.Goudreault, L.M.D'Ambrosio, M.J.Kean, M.J.Mullin, B.G.Larsen, A.Sanchez, S.Chaudhry, G.I.Chen, F.Sicheri, A.I.Nesvizhskii, R.Aebersold, B.Raught, and A.C.Gingras (2009).
A PP2A phosphatase high density interaction network identifies a novel striatin-interacting phosphatase and kinase complex linked to the cerebral cavernous malformation 3 (CCM3) protein.
  Mol Cell Proteomics, 8, 157-171.  
19592665 M.R.Swingle, L.Amable, B.G.Lawhorn, S.B.Buck, C.P.Burke, P.Ratti, K.L.Fischer, D.L.Boger, and R.E.Honkanen (2009).
Structure-activity relationship studies of fostriecin, cytostatin, and key analogs, with PP1, PP2A, PP5, and( beta12-beta13)-chimeras (PP1/PP2A and PP5/PP2A), provide further insight into the inhibitory actions of fostriecin family inhibitors.
  J Pharmacol Exp Ther, 331, 45-53.  
18992256 M.S.Kelker, R.Page, and W.Peti (2009).
Crystal structures of protein phosphatase-1 bound to nodularin-R and tautomycin: a novel scaffold for structure-based drug design of serine/threonine phosphatase inhibitors.
  J Mol Biol, 385, 11-21.
PDB codes: 3e7a 3e7b
19535438 S.Li, C.Brignole, R.Marcellus, S.Thirlwell, O.Binda, M.J.McQuoid, D.Ashby, H.Chan, Z.Zhang, M.J.Miron, D.C.Pallas, and P.E.Branton (2009).
The adenovirus E4orf4 protein induces G2/M arrest and cell death by blocking protein phosphatase 2A activity regulated by the B55 subunit.
  J Virol, 83, 8340-8352.  
19277525 Y.Shi (2009).
Assembly and structure of protein phosphatase 2A.
  Sci China C Life Sci, 52, 135-146.  
19879837 Y.Shi (2009).
Serine/threonine phosphatases: mechanism through structure.
  Cell, 139, 468-484.  
19747079 Z.Li, and J.B.Stock (2009).
Protein carboxyl methylation and the biochemistry of memory.
  Biol Chem, 390, 1087-1096.  
18488168 B.Wang, P.Zhang, and Q.Wei (2008).
Recent progress on the structure of Ser/Thr protein phosphatases.
  Sci China C Life Sci, 51, 487-494.  
17803193 D.L.Lizotte, J.J.Blakeslee, A.Siryaporn, J.T.Heath, and A.DeLong (2008).
A PP2A active site mutant impedes growth and causes misregulation of native catalytic subunit expression.
  J Cell Biochem, 103, 1309-1325.  
17967874 G.P.Shouse, X.Cai, and X.Liu (2008).
Serine 15 phosphorylation of p53 directs its interaction with B56gamma and the tumor suppressor activity of B56gamma-specific protein phosphatase 2A.
  Mol Cell Biol, 28, 448-456.  
18448228 J.Z.Wang, and F.Liu (2008).
Microtubule-associated protein tau in development, degeneration and protection of neurons.
  Prog Neurobiol, 85, 148-175.  
18211894 L.Yan, V.A.Lavin, L.R.Moser, Q.Cui, C.Kanies, and E.Yang (2008).
PP2A regulates the pro-apoptotic activity of FOXO1.
  J Biol Chem, 283, 7411-7420.  
19037259 N.Jin, C.Y.Chow, L.Liu, S.N.Zolov, R.Bronson, M.Davisson, J.L.Petersen, Y.Zhang, S.Park, J.E.Duex, D.Goldowitz, M.H.Meisler, and L.S.Weisman (2008).
VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P(2) in yeast and mouse.
  EMBO J, 27, 3221-3234.  
18596935 S.Ortega-Gutiérrez, D.Leung, S.Ficarro, E.C.Peters, and B.F.Cravatt (2008).
Targeted disruption of the PME-1 gene causes loss of demethylated PP2A and perinatal lethality in mice.
  PLoS ONE, 3, e2486.  
18253812 T.Golden, M.Swingle, and R.E.Honkanen (2008).
The role of serine/threonine protein phosphatase type 5 (PP5) in the regulation of stress-induced signaling networks and cancer.
  Cancer Metastasis Rev, 27, 169-178.  
18291659 V.Janssens, S.Longin, and J.Goris (2008).
PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail).
  Trends Biochem Sci, 33, 113-121.  
18394995 Y.Xing, Z.Li, Y.Chen, J.B.Stock, P.D.Jeffrey, and Y.Shi (2008).
Structural mechanism of demethylation and inactivation of protein phosphatase 2A.
  Cell, 133, 154-163.
PDB codes: 3c5v 3c5w
18922469 Y.Xu, Y.Chen, P.Zhang, P.D.Jeffrey, and Y.Shi (2008).
Structure of a protein phosphatase 2A holoenzyme: insights into B55-mediated Tau dephosphorylation.
  Mol Cell, 31, 873-885.
PDB code: 3dw8
17325038 C.S.Yang, H.W.Xin, J.B.Kelley, A.Spencer, D.L.Brautigan, and B.M.Paschal (2007).
Ligand binding to the androgen receptor induces conformational changes that regulate phosphatase interactions.
  Mol Cell Biol, 27, 3390-3404.  
17318227 G.B.Moorhead, L.Trinkle-Mulcahy, and A.Ulke-Lemée (2007).
Emerging roles of nuclear protein phosphatases.
  Nat Rev Mol Cell Biol, 8, 234-244.  
17939754 L.Ni, M.S.Swingle, A.C.Bourgeois, and R.E.Honkanen (2007).
High yield expression of serine/threonine protein phosphatase type 5, and a fluorescent assay suitable for use in the detection of catalytic inhibitors.
  Assay Drug Dev Technol, 5, 645-653.  
17632053 M.Mumby (2007).
PP2A: unveiling a reluctant tumor suppressor.
  Cell, 130, 21-24.  
17635907 S.Longin, K.Zwaenepoel, J.V.Louis, S.Dilworth, J.Goris, and V.Janssens (2007).
Selection of protein phosphatase 2A regulatory subunits is mediated by the C terminus of the catalytic Subunit.
  J Biol Chem, 282, 26971-26980.  
17608567 U.S.Cho, S.Morrone, A.A.Sablina, J.D.Arroyo, W.C.Hahn, and W.Xu (2007).
Structural basis of PP2A inhibition by small t antigen.
  PLoS Biol, 5, e202.  
17529992 Y.Chen, Y.Xu, Q.Bao, Y.Xing, Z.Li, Z.Lin, J.B.Stock, P.D.Jeffrey, and Y.Shi (2007).
Structural and biochemical insights into the regulation of protein phosphatase 2A by small t antigen of SV40.
  Nat Struct Mol Biol, 14, 527-534.
PDB code: 2pkg
17174897 Y.Xu, Y.Xing, Y.Chen, Y.Chao, Z.Lin, E.Fan, J.W.Yu, S.Strack, P.D.Jeffrey, and Y.Shi (2006).
Structure of the protein phosphatase 2A holoenzyme.
  Cell, 127, 1239-1251.
PDB codes: 2npp 2nyl 2nym
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.