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PDBsum entry 1wch

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Hydrolase PDB id
1wch
Jmol
Contents
Protein chain
308 a.a. *
Ligands
PO4 ×3
Waters ×280
* Residue conservation analysis
PDB id:
1wch
Name: Hydrolase
Title: Crystal structure of ptpl1 human tyrosine phosphatase mutated in colorectal cancer - evidence for a second phosphotyrosine substrate recognition pocket
Structure: Protein tyrosine phosphatase, non-receptor type 13. Chain: a. Fragment: residues 2163-2477. Synonym: protein tyrosine phosphatase like 1, protein tyrosine phosphatase 1e, ptp-e1, hptpe1, ptp-bas, protein tyrosine phosphatase ptpl1, fas-associated protein tyrosine phosphatase 1, fap-1. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 511693.
Resolution:
1.85Å     R-factor:   0.177     R-free:   0.204
Authors: F.Villa,M.Deak,G.B.Bloomberg,D.R.Alessi,D.M.F.Van Aalten
Key ref:
F.Villa et al. (2005). Crystal structure of the PTPL1/FAP-1 human tyrosine phosphatase mutated in colorectal cancer: evidence for a second phosphotyrosine substrate recognition pocket. J Biol Chem, 280, 8180-8187. PubMed id: 15611135 DOI: 10.1074/jbc.M412211200
Date:
16-Nov-04     Release date:   14-Dec-04    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q12923  (PTN13_HUMAN) -  Tyrosine-protein phosphatase non-receptor type 13
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
 
Seq:
Struc:
2485 a.a.
308 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.1.3.48  - Protein-tyrosine-phosphatase.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Protein tyrosine phosphate + H2O = protein tyrosine + phosphate
Protein tyrosine phosphate
+ H(2)O
= protein tyrosine
+
phosphate
Bound ligand (Het Group name = PO4)
corresponds exactly
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     dephosphorylation   2 terms 
  Biochemical function     phosphatase activity     2 terms  

 

 
    reference    
 
 
DOI no: 10.1074/jbc.M412211200 J Biol Chem 280:8180-8187 (2005)
PubMed id: 15611135  
 
 
Crystal structure of the PTPL1/FAP-1 human tyrosine phosphatase mutated in colorectal cancer: evidence for a second phosphotyrosine substrate recognition pocket.
F.Villa, M.Deak, G.B.Bloomberg, D.R.Alessi, D.M.van Aalten.
 
  ABSTRACT  
 
Protein-tyrosine phosphatase-L1 (PTPL1, also known as FAP-1, PTP1E, PTP-BAS, and PTPN13) is mutated in a significant number of colorectal tumors and may play a role in down-regulating signaling responses mediated by phosphatidylinositol 3-kinase, although the precise substrates are as yet unknown. In this study, we describe a 1.8 A resolution crystal structure of a fully active fragment of PTPL1 encompassing the catalytic domain. PTPL1 adopts the standard PTP fold, albeit with an unusually positioned additional N-terminal helix, and shows an ordered phosphate in the active site. Interestingly, a positively charged pocket is located near the PTPL1 catalytic site, reminiscent of the second phosphotyrosine binding site in PTP1B, which is required to dephosphorylate peptides containing two adjacent phosphotyrosine residues (as occurs for example in the activated insulin receptor). We demonstrate that PTPL1, like PTP1B, interacts with and dephosphorylates a bis-phosphorylated insulin receptor peptide more efficiently than monophosphorylated peptides, indicating that PTPL1 may down-regulate the phosphatidylinositol 3-kinase pathway, by dephosphorylating insulin or growth factor receptors that contain tandem phosphotyrosines. The structure also reveals that four out of five PTPL1 mutations found in colorectal cancers are located on solvent-exposed regions remote from the active site, consistent with these mutants being normally active. In contrast, the fifth mutation, which changes Met-2307 to Thr, is close to the active site cysteine and decreases activity significantly. Our studies provide the first molecular description of the PTPL1 catalytic domain and give new insight into the function of PTPL1.
 
  Selected figure(s)  
 
Figure 1.
FIG. 1. Comparison of the structure of the catalytic domain of PTPL1 and PTP1B. A, overall ribbon structure of the PTPL1 catalytic domain (residues 2152-2485) phosphate complex (left panel). A 2 F[o] - F[c], [calc] electron density map for the phosphate molecule is drawn in red and displays well ordered density. The key features of the structure that are described under the Introduction are indicated in magenta. The N-terminal 0 helix that replaces the 7 helix on PTP1B is displayed in yellow. Shown in stick representation are Cys-2408, Asp-2378, Arg-2205, Ile-2458, and Met-2307. The electrostatic potential of the surface of PTPL1 and the location of the positively charged primary and secondary phosphotyrosine binding pockets are indicated (right panel). The blue areas (+6kT) represent highly positively charged residues, and the red areas (-6kT) represent highly negatively charged residues. B, overall ribbon structure of the PTP1B catalytic domain (residues 1-298, left panel). The electrostatic potential of the surface of PTP1B, calculated without the peptide bound to the enzyme, complexed to the phosphorylated insulin receptor peptide phosphorylated at residues equivalent to Tyr-1162 and Tyr-1163 on the insulin receptor that are located in the primary and secondary phosphotyrosine binding pockets, respectively is shown in the right panel.
Figure 3.
FIG. 3. Comparison of the catalytic and secondary phosphotyrosine binding site of PTPL1 and PTP1B. A, a ribbon drawing of the catalytic center of PTPL1 displaying the electron density of the phosphate molecule shown in red. Shown in stick representation are Cys-2408; Asp-2378 in the WPD loop; Gln-2452 from the Q-loop. Also shown are the His-2448, Gln-2221, Gly-2449, and Arg-2444 that make up the secondary phosphotyrosine binding pocket. Superimposed on the structure is a model of how the phosphorylated insulin receptor peptide (ETDY(P)Y(P)R) might interact with PTPL1 based on the structure of this peptide with PTP1B. B, a ribbon drawing of the catalytic center of PTP1B complexed to the phosphorylated insulin receptor peptide (ETDY(P)Y(P)R). Shown in stick representation are Ser-215 (replacing the catalytic cysteine in trapping mutant PTP1B-C215S); Asp-181 in the WPD loop; Gln-262 from the Q-loop. Also shown are the Arg-24, Met-258, Gly-259, and Arg-254 in the secondary phosphotyrosine binding pocket. Note that His-2448 located on the loop between 5 and 6 in PTPL1 is structurally replacing Arg-24 in PTP1B located on the 2'-helix.
 
  The above figures are reprinted by permission from the ASBMB: J Biol Chem (2005, 280, 8180-8187) copyright 2005.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21204784 S.Wullschleger, D.H.Wasserman, A.Gray, K.Sakamoto, and D.R.Alessi (2011).
Role of TAPP1 and TAPP2 adaptor binding to PtdIns(3,4)P2 in regulating insulin sensitivity defined by knock-in analysis.
  Biochem J, 434, 265-274.  
19672627 Y.Mita, Y.Yasuda, A.Sakai, H.Yamamoto, S.Toyooka, M.Gunduz, S.Tanabe, Y.Naomoto, M.Ouchida, and K.Shimizu (2010).
Missense polymorphisms of PTPRJ and PTPN13 genes affect susceptibility to a variety of human cancers.
  J Cancer Res Clin Oncol, 136, 249-259.  
19734941 A.C.Hoover, G.L.Strand, P.N.Nowicki, M.E.Anderson, P.D.Vermeer, A.J.Klingelhutz, A.D.Bossler, J.V.Pottala, W.J.Hendriks, and J.H.Lee (2009).
Impaired PTPN13 phosphatase activity in spontaneous or HPV-induced squamous cell carcinomas potentiates oncogene signaling through the MAP kinase pathway.
  Oncogene, 28, 3960-3970.  
19167335 A.J.Barr, E.Ugochukwu, W.H.Lee, O.N.King, P.Filippakopoulos, I.Alfano, P.Savitsky, N.A.Burgess-Brown, S.Müller, and S.Knapp (2009).
Large-scale structural analysis of the classical human protein tyrosine phosphatome.
  Cell, 136, 352-363.
PDB codes: 2ahs 2b49 2cfv 2cjz 2gjt 2h4v 2i75 2jjd 2nlk 2nz6 2oc3 2ooq 2p6x 2pa5 2qep 3b7o
18298793 L.Tabernero, A.R.Aricescu, E.Y.Jones, and S.E.Szedlacsek (2008).
Protein tyrosine phosphatases: structure-function relationships.
  FEBS J, 275, 867-882.  
18265946 O.D.Abaan, and J.A.Toretsky (2008).
PTPL1: a large phosphatase with a split personality.
  Cancer Metastasis Rev, 27, 205-214.  
18160445 W.C.Spanos, A.Hoover, G.F.Harris, S.Wu, G.L.Strand, M.E.Anderson, A.J.Klingelhutz, W.Hendriks, A.D.Bossler, and J.H.Lee (2008).
The PDZ binding motif of human papillomavirus type 16 E6 induces PTPN13 loss, which allows anchorage-independent growth and synergizes with ras for invasive growth.
  J Virol, 82, 2493-2500.  
17567745 A.A.Puhl, R.J.Gruninger, R.Greiner, T.W.Janzen, S.C.Mosimann, and L.B.Selinger (2007).
Kinetic and structural analysis of a bacterial protein tyrosine phosphatase-like myo-inositol polyphosphatase.
  Protein Sci, 16, 1368-1378.
PDB codes: 2b4o 2b4p 2b4u
17437721 C.Grundner, D.Perrin, R.Hooft van Huijsduijnen, D.Swinnen, J.Gonzalez, C.L.Gee, T.N.Wells, and T.Alber (2007).
Structural basis for selective inhibition of Mycobacterium tuberculosis protein tyrosine phosphatase PtpB.
  Structure, 15, 499-509.
PDB code: 2oz5
17057754 P.Cohen (2006).
The twentieth century struggle to decipher insulin signalling.
  Nat Rev Mol Cell Biol, 7, 867-873.  
16271885 C.Grundner, H.L.Ng, and T.Alber (2005).
Mycobacterium tuberculosis protein tyrosine phosphatase PtpB structure reveals a diverged fold and a buried active site.
  Structure, 13, 1625-1634.
PDB code: 1ywf
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.