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protein Protein-protein interface(s) links
Hydrolase PDB id
3c5w
Jmol
Contents
Protein chains
228 a.a. *
294 a.a. *
294 a.a. *
Waters ×62
* Residue conservation analysis
PDB id:
3c5w
Name: Hydrolase
Title: Complex between pp2a-specific methylesterase pme-1 and pp2a enzyme
Structure: Pp2a a subunit. Chain: a. Engineered: yes. Pp2a c subunit. Chain: c. Engineered: yes. Pp2a-specific methylesterase pme-1. Chain: p. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_taxid: 562
Resolution:
2.80Å     R-factor:   0.198     R-free:   0.263
Authors: Y.Xing,Z.Li,Y.Chen,J.Stock,P.D.Jeffrey,Y.Shi
Key ref:
Y.Xing et al. (2008). Structural mechanism of demethylation and inactivation of protein phosphatase 2A. Cell, 133, 154-163. PubMed id: 18394995 DOI: 10.1016/j.cell.2008.02.041
Date:
01-Feb-08     Release date:   15-Apr-08    
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.
228 a.a.*
Protein chain
Pfam   ArchSchema ?
P67775  (PP2AA_HUMAN) -  Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform
Seq:
Struc: 		309 a.a.
294 a.a.
Protein chain
Pfam   ArchSchema ?
Q9Y570  (PPME1_HUMAN) -  Protein phosphatase methylesterase 1
Seq:
Struc: 		386 a.a.
294 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 32 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class 1: 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
   Enzyme class 2: Chain P: E.C.3.1.1.89
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.
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   29 terms 
  Biochemical function     binding     8 terms  

 

 
    Added reference    
 
 
DOI no: 10.1016/j.cell.2008.02.041 Cell 133:154-163 (2008)
PubMed id: 18394995  
 
 
Structural mechanism of demethylation and inactivation of protein phosphatase 2A.
Y.Xing, Z.Li, Y.Chen, J.B.Stock, P.D.Jeffrey, Y.Shi.
 
  ABSTRACT  
 
Protein phosphatase 2A (PP2A) is an important serine/threonine phosphatase that plays a role in many biological processes. Reversible carboxyl methylation of the PP2A catalytic subunit is an essential regulatory mechanism for its function. Demethylation and negative regulation of PP2A is mediated by a PP2A-specific methylesterase PME-1, which is conserved from yeast to humans. However, the underlying mechanism of PME-1 function remains enigmatic. Here we report the crystal structures of PME-1 by itself and in complex with a PP2A heterodimeric core enzyme. The structures reveal that PME-1 directly binds to the active site of PP2A and that this interaction results in the activation of PME-1 by rearranging the catalytic triad into an active conformation. Strikingly, these interactions also lead to inactivation of PP2A by evicting the manganese ions that are required for the phosphatase activity of PP2A. These observations identify a dual role of PME-1 that regulates PP2A activation, methylation, and holoenzyme assembly in cells.
 
  Selected figure(s)  
 
Figure 3.
Figure 3. Interface between PME-1 and the C Subunit of the PP2A Core Enzyme
(A) PME-1 and the C subunit form an S-shaped interface. A slice of the complex is shown.
(B) A close-up view of the interface in stereo. Residues from PME-1 and the C subunit are shown in green and magenta, respectively. H-bonds are represented by dotted lines. 		Figure 5.
Figure 5. Inactivation of PP2A by PME-1
(A) A stereo view of the PME-1-PP2A interface at the active site region of the C subunit. 2Fo-Fc electron density is shown at 1.5σ level surrounding side chains of Met335 in PME-1 and the residues that are involved in binding to metal atoms in the C subunit.
(B) Structural overlay of the PME-1-PP2A interface with the active site of the C subunit in the PP2A core enzyme. The C subunit in the PP2A core enzyme is colored cyan, with the side chains shown in gold. The two manganese metal atoms and okadaic acid are colored gray.
 
  The above figures are reprinted by permission from Cell Press: Cell (2008, 133, 154-163) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21398589 D.A.Bachovchin, J.T.Mohr, A.E.Speers, C.Wang, J.M.Berlin, T.P.Spicer, V.Fernandez-Vega, P.Chase, P.S.Hodder, S.C.Schürer, D.K.Nomura, H.Rosen, G.C.Fu, and B.F.Cravatt (2011).
Academic cross-fertilization by public screening yields a remarkable class of protein phosphatase methylesterase-1 inhibitors.
  Proc Natl Acad Sci U S A, 108, 6811-6816.  
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
21044074 J.M.Sontag, V.Nunbhakdi-Craig, M.Mitterhuber, E.Ogris, and E.Sontag (2010).
Regulation of protein phosphatase 2A methylation by LCMT1 and PME-1 plays a critical role in differentiation of neuroblastoma cells.
  J Neurochem, 115, 1455-1465.  
20643941 J.van Eersel, Y.D.Ke, X.Liu, F.Delerue, J.J.Kril, J.Götz, and L.M.Ittner (2010).
Sodium selenate mitigates tau pathology, neurodegeneration, and functional deficits in Alzheimer's disease models.
  Proc Natl Acad Sci U S A, 107, 13888-13893.  
19822598 M.Wang, L.L.Chan, M.Si, H.Hong, and D.Wang (2010).
Proteomic analysis of hepatic tissue of zebrafish (Danio rerio) experimentally exposed to chronic microcystin-LR.
  Toxicol Sci, 113, 60-69.  
20636478 S.Finnegan, A.M.Mackey, and T.G.Cotter (2010).
A stress survival response in retinal cells mediated through inhibition of the serine/threonine phosphatase PP2A.
  Eur J Neurosci, 32, 322-334.  
19198594 A.Wepf, T.Glatter, A.Schmidt, R.Aebersold, and M.Gstaiger (2009).
Quantitative interaction proteomics using mass spectrometry.
  Nat Methods, 6, 203-205.  
19701246 C.H.Switzer, L.A.Ridnour, R.Y.Cheng, A.Sparatore, P.Del Soldato, T.W.Moody, M.P.Vitek, D.D.Roberts, and D.A.Wink (2009).
Dithiolethione compounds inhibit Akt signaling in human breast and lung cancer cells by increasing PP2A activity.
  Oncogene, 28, 3837-3846.  
19285938 D.M.Virshup, and S.Shenolikar (2009).
From promiscuity to precision: protein phosphatases get a makeover.
  Mol Cell, 33, 537-545.  
19818709 M.Kong, D.Ditsworth, T.Lindsten, and C.B.Thompson (2009).
Alpha4 is an essential regulator of PP2A phosphatase activity.
  Mol Cell, 36, 51-60.  
19293187 P.Puustinen, M.R.Junttila, S.Vanhatupa, A.A.Sablina, M.E.Hector, K.Teittinen, O.Raheem, K.Ketola, S.Lin, J.Kast, H.Haapasalo, W.C.Hahn, and J.Westermarck (2009).
PME-1 protects extracellular signal-regulated kinase pathway activity from protein phosphatase 2A-mediated inactivation in human malignant glioma.
  Cancer Res, 69, 2870-2877.  
19004810 Q.Wang (2009).
PP2A: a new link between peroxynitrite and endothelial barrier dysfunction?
  Cardiovasc Res, 81, 5-6.  
19156129 T.Glatter, A.Wepf, R.Aebersold, and M.Gstaiger (2009).
An integrated workflow for charting the human interaction proteome: insights into the PP2A system.
  Mol Syst Biol, 5, 237.  
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.  
18987184 J.M.Sontag, V.Nunbhakdi-Craig, L.Montgomery, E.Arning, T.Bottiglieri, and E.Sontag (2008).
Folate deficiency induces in vitro and mouse brain region-specific downregulation of leucine carboxyl methyltransferase-1 and protein phosphatase 2A B(alpha) subunit expression that correlate with enhanced tau phosphorylation.
  J Neurosci, 28, 11477-11487.  
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 code is shown on the right.