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PDBsum entry 1lw3

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protein ligands links
Hydrolase PDB id
1lw3
Jmol
Contents
Protein chain
513 a.a. *
Ligands
PO4 ×3
Waters ×274
* Residue conservation analysis
PDB id:
1lw3
Name: Hydrolase
Title: Crystal structure of myotubularin-related protein 2 complexed with phosphate
Structure: Myotubularin-related protein 2. Chain: a. Fragment: ph and phosphatase domains (residues 1-643). Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: mtmr2. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Resolution:
2.30Å     R-factor:   0.209     R-free:   0.273
Authors: M.J.Begley,G.S.Taylor,S.-A.Kim,D.M.Veine,J.E.Dixon, J.A.Stuckey
Key ref:
M.J.Begley et al. (2003). Crystal structure of a phosphoinositide phosphatase, MTMR2: insights into myotubular myopathy and Charcot-Marie-Tooth syndrome. Mol Cell, 12, 1391-1402. PubMed id: 14690594 DOI: 10.1016/S1097-2765(03)00486-6
Date:
30-May-02     Release date:   07-Oct-03    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q13614  (MTMR2_HUMAN) -  Myotubularin-related protein 2
Seq:
Struc:
 
Seq:
Struc:
643 a.a.
513 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class 2: E.C.3.1.3.64  - Phosphatidylinositol-3-phosphatase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: 1-phosphatidyl-1D-myo-inositol 3-phosphate + H2O = 1-phosphatidyl- 1D-myo-inositol + phosphate
1-phosphatidyl-1D-myo-inositol 3-phosphate
+ H(2)O
= 1-phosphatidyl- 1D-myo-inositol
+ phosphate
   Enzyme class 3: E.C.3.1.3.95  - Phosphatidylinositol-3,5-bisphosphate 3-phosphatase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: 1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate + H2O = 1-phosphatidyl- 1D-myo-inositol 5-phosphate + phosphate
1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate
+ H(2)O
= 1-phosphatidyl- 1D-myo-inositol 5-phosphate
+ phosphate
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     synaptic membrane   14 terms 
  Biological process     peptidyl-tyrosine dephosphorylation   20 terms 
  Biochemical function     phosphatidylinositol-3,5-bisphosphate 3-phosphatase activity     8 terms  

 

 
    reference    
 
 
DOI no: 10.1016/S1097-2765(03)00486-6 Mol Cell 12:1391-1402 (2003)
PubMed id: 14690594  
 
 
Crystal structure of a phosphoinositide phosphatase, MTMR2: insights into myotubular myopathy and Charcot-Marie-Tooth syndrome.
M.J.Begley, G.S.Taylor, S.A.Kim, D.M.Veine, J.E.Dixon, J.A.Stuckey.
 
  ABSTRACT  
 
Myotubularin-related proteins are a large subfamily of protein tyrosine phosphatases (PTPs) that dephosphorylate D3-phosphorylated inositol lipids. Mutations in members of the myotubularin family cause the human neuromuscular disorders myotubular myopathy and type 4B Charcot-Marie-Tooth syndrome. The crystal structure of a representative member of this family, MTMR2, reveals a phosphatase domain that is structurally unique among PTPs. A series of mutants are described that exhibit altered enzymatic activity and provide insight into the specificity of myotubularin phosphatases toward phosphoinositide substrates. The structure also reveals that the GRAM domain, found in myotubularin family phosphatases and predicted to occur in approximately 180 proteins, is part of a larger motif with a pleckstrin homology (PH) domain fold. Finally, the MTMR2 structure will serve as a model for other members of the myotubularin family and provide a framework for understanding the mechanism whereby mutations in these proteins lead to disease.
 
  Selected figure(s)  
 
Figure 5.
Figure 5. Model of Ins(1,3,5)P[3] in the Active Site of MTMR2(A) A schematic of the phosphate molecules and hydrogen bond network in the MTMR2 active site. Hydrogen bonds are shown as blue dotted lines.(B) Model of Ins(1,3,5)P[3] in the active site of MTMR2 with its D1 and D3 phosphate groups superimposed onto the phosphate molecules shown in (A).(C) Phosphatase activity of MTMR2 mutants toward PI(3)P and PI(3,5)P[2] substrates. Values are expressed as percent wild-type MTMR2 activity of three independent experiments (mean ± SEM).
Figure 6.
Figure 6. Missense Disease Mutations(A) Sequence conservation of MTM1 and MTMR2 and the location of missense disease mutations. The sequence of MTMR2 corresponding to the crystal structure was aligned with MTM1. Regions of identity are boxed and shaded. Arrows and ovals represent β strands and α helices, respectively. Missense disease mutations are marked with arrowheads.(B) Van der Waals surface space-filled model of MTMR2. The view is the same as Figure 2A. The PH-GRAM domain is shown in green, the phosphatase domain in blue, and the active site motif (P loop) in yellow. Residues that are sites of missense disease mutations are red and labeled when >10% solvent accessible.(C) View corresponding to a 180° rotation around a vertical axis with respect to Figure 6B. Solvent accessible residues are indicated.
 
  The above figures are reprinted by permission from Cell Press: Mol Cell (2003, 12, 1391-1402) copyright 2003.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21135508 K.Hnia, H.Tronchère, K.K.Tomczak, L.Amoasii, P.Schultz, A.H.Beggs, B.Payrastre, J.L.Mandel, and J.Laporte (2011).
Myotubularin controls desmin intermediate filament architecture and mitochondrial dynamics in human and mouse skeletal muscle.
  J Clin Invest, 121, 70-85.  
20389282 A.Manford, T.Xia, A.K.Saxena, C.Stefan, F.Hu, S.D.Emr, and Y.Mao (2010).
Crystal structure of the yeast Sac1: implications for its phosphoinositide phosphatase function.
  EMBO J, 29, 1489-1498.
PDB code: 3lwt
20679247 C.W.Vander Kooi, A.O.Taylor, R.M.Pace, D.A.Meekins, H.F.Guo, Y.Kim, and M.S.Gentry (2010).
Structural basis for the glucan phosphatase activity of Starch Excess4.
  Proc Natl Acad Sci U S A, 107, 15379-15384.
PDB code: 3nme
20576132 D.Kerk, and G.B.Moorhead (2010).
A phylogenetic survey of myotubularin genes of eukaryotes: distribution, protein structure, evolution, and gene expression.
  BMC Evol Biol, 10, 196.  
19009368 C.Bieniossek, and I.Berger (2009).
Towards eukaryotic structural complexomics.
  J Struct Funct Genomics, 10, 37-46.  
19754155 S.Hsu, Y.Kim, S.Li, E.S.Durrant, R.M.Pace, V.L.Woods, and M.S.Gentry (2009).
Structural insights into glucan phosphatase dynamics using amide hydrogen-deuterium exchange mass spectrometry.
  Biochemistry, 48, 9891-9902.  
19580826 T.Sasaki, S.Takasuga, J.Sasaki, S.Kofuji, S.Eguchi, M.Yamazaki, and A.Suzuki (2009).
Mammalian phosphoinositide kinases and phosphatases.
  Prog Lipid Res, 48, 307-343.  
18429927 A.S.Nicot, and J.Laporte (2008).
Endosomal phosphoinositides and human diseases.
  Traffic, 9, 1240-1249.  
17973976 D.Goryunov, A.Nightingale, L.Bornfleth, C.Leung, and R.K.Liem (2008).
Multiple disease-linked myotubularin mutations cause NFL assembly defects in cultured cells and disrupt myotubularin dimerization.
  J Neurochem, 104, 1536-1552.  
18298792 R.Pulido, and R.Hooft van Huijsduijnen (2008).
Protein tyrosine phosphatases: dual-specificity phosphatases in health and disease.
  FEBS J, 275, 848-866.  
17917119 A.Bolis, P.Zordan, S.Coviello, and A.Bolino (2007).
Myotubularin-related (MTMR) phospholipid phosphatase proteins in the peripheral nervous system.
  Mol Neurobiol, 35, 308-316.  
17997094 E.Caro, and C.Gutierrez (2007).
A green GEM: intriguing analogies with animal geminin.
  Trends Cell Biol, 17, 580-585.  
17574030 M.V.Nachury, A.V.Loktev, Q.Zhang, C.J.Westlake, J.Peränen, A.Merdes, D.C.Slusarski, R.H.Scheller, J.F.Bazan, V.C.Sheffield, and P.K.Jackson (2007).
A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis.
  Cell, 129, 1201-1213.  
18039372 R.Brenchley, H.Tariq, H.McElhinney, B.Szöor, J.Huxley-Jones, R.Stevens, K.Matthews, and L.Tabernero (2007).
The TriTryp phosphatome: analysis of the protein phosphatase catalytic domains.
  BMC Genomics, 8, 434.  
17427953 S.K.Jung, D.G.Jeong, T.S.Yoon, J.H.Kim, S.E.Ryu, and S.J.Kim (2007).
Crystal structure of human slingshot phosphatase 2.
  Proteins, 68, 408-412.
PDB code: 2nt2
16689637 J.H.Hurley, and S.D.Emr (2006).
The ESCRT complexes: structure and mechanism of a membrane-trafficking network.
  Annu Rev Biophys Biomol Struct, 35, 277-298.  
16410353 M.J.Begley, G.S.Taylor, M.A.Brock, P.Ghosh, V.L.Woods, and J.E.Dixon (2006).
Molecular basis for substrate recognition by MTMR2, a myotubularin family phosphoinositide phosphatase.
  Proc Natl Acad Sci U S A, 103, 927-932.
PDB codes: 1zsq 1zvr
16914545 P.Choudhury, S.Srivastava, Z.Li, K.Ko, M.Albaqumi, K.Narayan, W.A.Coetzee, M.A.Lemmon, and E.Y.Skolnik (2006).
Specificity of the myotubularin family of phosphatidylinositol-3-phosphatase is determined by the PH/GRAM domain.
  J Biol Chem, 281, 31762-31769.  
15998640 F.L.Robinson, and J.E.Dixon (2005).
The phosphoinositide-3-phosphatase MTMR2 associates with MTMR13, a membrane-associated pseudophosphatase also mutated in type 4B Charcot-Marie-Tooth disease.
  J Biol Chem, 280, 31699-31707.  
16262718 M.J.Clague, and O.Lorenzo (2005).
The myotubularin family of lipid phosphatases.
  Traffic, 6, 1063-1069.  
15755741 T.Slagsvold, R.Aasland, S.Hirano, K.G.Bache, C.Raiborg, D.Trambaiolo, S.Wakatsuki, and H.Stenmark (2005).
Eap45 in mammalian ESCRT-II binds ubiquitin via a phosphoinositide-interacting GLUE domain.
  J Biol Chem, 280, 19600-19606.  
16365163 T.Strahl, H.Hama, D.B.DeWald, and J.Thorner (2005).
Yeast phosphatidylinositol 4-kinase, Pik1, has essential roles at the Golgi and in the nucleus.
  J Cell Biol, 171, 967-979.  
15574876 V.A.Sciorra, A.Audhya, A.B.Parsons, N.Segev, C.Boone, and S.D.Emr (2005).
Synthetic genetic array analysis of the PtdIns 4-kinase Pik1p identifies components in a Golgi-specific Ypt31/rab-GTPase signaling pathway.
  Mol Biol Cell, 16, 776-793.  
15201283 A.Alonso, S.Burkhalter, J.Sasin, L.Tautz, J.Bogetz, H.Huynh, M.C.Bremer, L.J.Holsinger, A.Godzik, and T.Mustelin (2004).
The minimal essential core of a cysteine-based protein-tyrosine phosphatase revealed by a novel 16-kDa VH1-like phosphatase, VHZ.
  J Biol Chem, 279, 35768-35774.  
15457207 D.Komander, A.Fairservice, M.Deak, G.S.Kular, A.R.Prescott, C.Peter Downes, S.T.Safrany, D.R.Alessi, and D.M.van Aalten (2004).
Structural insights into the regulation of PDK1 by phosphoinositides and inositol phosphates.
  EMBO J, 23, 3918-3928.
PDB codes: 1w1d 1w1g 1w1h
15128740 W.Q.Wang, J.Bembenek, K.R.Gee, H.Yu, H.Charbonneau, and Z.Y.Zhang (2004).
Kinetic and mechanistic studies of a cell cycle protein phosphatase Cdc14.
  J Biol Chem, 279, 30459-30468.  
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.