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PDBsum entry 3dw8

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protein ligands metals Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
3dw8
Jmol
Contents
Protein chains
582 a.a. *
421 a.a. *
288 a.a. *
Ligands
DAL-LEU-ACB-ARG-
1ZN-FGA-DAM
×2
Metals
_MN ×4
* Residue conservation analysis
PDB id:
3dw8
Name: Hydrolase/hydrolase inhibitor
Title: Structure of a protein phosphatase 2a holoenzyme with b55 su
Structure: Serine/threonine-protein phosphatase 2a 65 kda re subunit a alpha isoform. Chain: a, d. Fragment: a delta 8: residues 9-589. Synonym: pp2a, subunit a, pr65-alpha isoform, pp2a, subunit alpha isoform, medium tumor antigen-associated 61 kda prote engineered: yes. Serine/threonine-protein phosphatase 2a 55 kda re subunit b alpha isoform.
Source: Homo sapiens. Organism_taxid: 9606. Gene: ppp2r1a. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: ppp2r2a. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Expression_system_cell_line: sf9.
Resolution:
2.85Å     R-factor:   0.228     R-free:   0.285
Authors: Y.Xu,Y.Chen,P.Zhang,P.D.Jeffrey,Y.Shi
Key ref:
Y.Xu et al. (2008). Structure of a protein phosphatase 2A holoenzyme: insights into B55-mediated Tau dephosphorylation. Mol Cell, 31, 873-885. PubMed id: 18922469 DOI: 10.1016/j.molcel.2008.08.006
Date:
21-Jul-08     Release date:   07-Oct-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P30153  (2AAA_HUMAN) -  Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform
Seq:
Struc:
 
Seq:
Struc:
589 a.a.
582 a.a.*
Protein chains
Pfam  
P63151  (2ABA_HUMAN) -  Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B alpha isoform
Seq:
Struc:
447 a.a.
421 a.a.*
Protein chains
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
* PDB and UniProt seqs differ at 2 residue positions (black crosses)

 Enzyme reactions 
   Enzyme class: Chains C, F: E.C.3.1.3.16  - Protein-serine/threonine phosphatase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: [a protein]-serine/threonine phosphate + H2O = [a protein]- serine/threonine + phosphate
[a protein]-serine/threonine phosphate
+ H(2)O
= [a protein]- serine/threonine
Bound ligand (Het Group name = DAM)
matches with 41.67% similarity
+ phosphate
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   14 terms 
  Biological process     positive regulation of extrinsic apoptotic signaling pathway in absence of ligand   39 terms 
  Biochemical function     antigen binding     11 terms  

 

 
    Key reference    
 
 
DOI no: 10.1016/j.molcel.2008.08.006 Mol Cell 31:873-885 (2008)
PubMed id: 18922469  
 
 
Structure of a protein phosphatase 2A holoenzyme: insights into B55-mediated Tau dephosphorylation.
Y.Xu, Y.Chen, P.Zhang, P.D.Jeffrey, Y.Shi.
 
  ABSTRACT  
 
Protein phosphatase 2A (PP2A) regulates many essential aspects of cellular physiology. Members of the regulatory B/B55/PR55 family are thought to play a key role in the dephosphorylation of Tau, whose hyperphosphorylation contributes to Alzheimer's disease. The underlying mechanisms of the PP2A-Tau connection remain largely enigmatic. Here, we report the complete reconstitution of a Tau dephosphorylation assay and the crystal structure of a heterotrimeric PP2A holoenzyme involving the regulatory subunit Balpha. We show that Balpha specifically and markedly facilitates dephosphorylation of the phosphorylated Tau in our reconstituted assay. The Balpha subunit comprises a seven-bladed beta propeller, with an acidic, substrate-binding groove located in the center of the propeller. The beta propeller latches onto the ridge of the PP2A scaffold subunit with the help of a protruding beta hairpin arm. Structure-guided mutagenesis studies revealed the underpinnings of PP2A-mediated dephosphorylation of Tau.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. Overall Structure of the Heterotrimeric PP2A Holoenzyme Involving the Bα Subunit
(A) Overall structure of the PP2A holoenzyme involving the Bα subunit and bound to MCLR. The scaffold (Aα), catalytic (Cα), and regulatory B (Bα) subunits are shown in yellow, green, and blue, respectively. MCLR is shown in magenta. Bα primarily interacts with Aα through an extensive interface. Cα interacts with Aα as described (Xing et al., 2006). Two views are shown here to reveal the essential features of the holoenzyme.
(B) The regulatory Bα subunit contains a highly acidic top face and a hairpin arm. The electrostatic surface potential of Bα is shown. Aα and Cα are shown in backbone worm.
(C) Comparison of the distinct conformations of the A subunit in the PP2A core enzyme and in the two holoenzymes. Figures 2B, 3C, and 5C were prepared using GRASP (Nicholls et al., 1991); all other structural figures were made using MOLSCRIPT (Kraulis, 1991).
Figure 4.
Figure 4. Specific Recognition of the B Subunit for the PP2A Scaffold Subunit
(A) A stereo view of the atomic interactions between the β2C-β2D hairpin arm of Bα and HEAT repeats 1 and 2 of Aα. This interface is dominated by van der Walls contacts.
(B) A stereo view of the recognition between the bottom face of Bα and HEAT repeats 3–7. This interface contains a number of hydrogen bonds, which are represented by red dashed lines.
(C) Structural comparison of the PP2A holoenzymes involving the regulatory B/B55/PR55 and B′/B56/PR61 subunits.
 
  The above figures are reprinted by permission from Cell Press: Mol Cell (2008, 31, 873-885) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21327254 C.Smet-Nocca, M.Broncel, J.M.Wieruszeski, C.Tokarski, X.Hanoulle, A.Leroy, I.Landrieu, C.Rolando, G.Lippens, and C.P.Hackenberger (2011).
Identification of O-GlcNAc sites within peptides of the Tau protein and their impact on phosphorylation.
  Mol Biosyst, 7, 1420-1429.  
21750572 C.Wurzenberger, and D.W.Gerlich (2011).
Phosphatases: providing safe passage through mitotic exit.
  Nat Rev Mol Cell Biol, 12, 469-482.  
21482799 J.V.Louis, E.Martens, P.Borghgraef, C.Lambrecht, W.Sents, S.Longin, K.Zwaenepoel, R.Pijnenborg, I.Landrieu, G.Lippens, B.Ledermann, J.Götz, F.Van Leuven, J.Goris, and V.Janssens (2011).
Mice lacking phosphatase PP2A subunit PR61/B'delta (Ppp2r5d) develop spatially restricted tauopathy by deregulation of CDK5 and GSK3beta.
  Proc Natl Acad Sci U S A, 108, 6957-6962.  
20133745 A.Grinthal, I.Adamovic, B.Weiner, M.Karplus, and N.Kleckner (2010).
PR65, the HEAT-repeat scaffold of phosphatase PP2A, is an elastic connector that links force and catalysis.
  Proc Natl Acad Sci U S A, 107, 2467-2472.  
20017541 A.Saraf, E.A.Oberg, and S.Strack (2010).
Molecular determinants for PP2A substrate specificity: charged residues mediate dephosphorylation of tyrosine hydroxylase by the PP2A/B' regulatory subunit.
  Biochemistry, 49, 986-995.  
20679486 B.Eroglu, D.Moskophidis, and N.F.Mivechi (2010).
Loss of Hsp110 leads to age-dependent tau hyperphosphorylation and early accumulation of insoluble amyloid beta.
  Mol Cell Biol, 30, 4626-4643.  
20451393 C.U.Stirnimann, E.Petsalaki, R.B.Russell, and C.W.Müller (2010).
WD40 proteins propel cellular networks.
  Trends Biochem Sci, 35, 565-574.  
20154705 D.H.Lee, Y.Pan, S.Kanner, P.Sung, J.A.Borowiec, and D.Chowdhury (2010).
A PP4 phosphatase complex dephosphorylates RPA2 to facilitate DNA repair via homologous recombination.
  Nat Struct Mol Biol, 17, 365-372.  
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.  
20711181 M.H.Schmitz, M.Held, V.Janssens, J.R.Hutchins, O.Hudecz, E.Ivanova, J.Goris, L.Trinkle-Mulcahy, A.I.Lamond, I.Poser, A.A.Hyman, K.Mechtler, J.M.Peters, and D.W.Gerlich (2010).
Live-cell imaging RNAi screen identifies PP2A-B55alpha and importin-beta1 as key mitotic exit regulators in human cells.
  Nat Cell Biol, 12, 886-893.  
21050448 P.J.Khandelwal, S.B.Dumanis, L.R.Feng, K.Maguire-Zeiss, G.Rebeck, H.A.Lashuel, and C.E.Moussa (2010).
Parkinson-related parkin reduces α-Synuclein phosphorylation in a gene transfer model.
  Mol Neurodegener, 5, 47.  
19285938 D.M.Virshup, and S.Shenolikar (2009).
From promiscuity to precision: protein phosphatases get a makeover.
  Mol Cell, 33, 537-545.  
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.  
19029245 M.J.Van Kanegan, and S.Strack (2009).
The protein phosphatase 2A regulatory subunits B'beta and B'delta mediate sustained TrkA neurotrophin receptor autophosphorylation and neuronal differentiation.
  Mol Cell Biol, 29, 662-674.  
19556239 W.Zhang, J.Yang, Y.Liu, X.Chen, T.Yu, J.Jia, and C.Liu (2009).
PR55 alpha, a regulatory subunit of PP2A, specifically regulates PP2A-mediated beta-catenin dephosphorylation.
  J Biol Chem, 284, 22649-22656.  
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.  
19716788 Z.Xu, B.Cetin, M.Anger, U.S.Cho, W.Helmhart, K.Nasmyth, and W.Xu (2009).
Structure and function of the PP2A-shugoshin interaction.
  Mol Cell, 35, 426-441.
PDB code: 3fga
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.