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J. Biol. Chem., Vol. 280, Issue 9, 8180-8187, March 4, 2005

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Crystal Structure of the PTPL1/FAP-1 Human Tyrosine Phosphatase Mutated in Colorectal Cancer

EVIDENCE FOR A SECOND PHOSPHOTYROSINE SUBSTRATE RECOGNITION POCKET^*

Fabrizio Villa¶, Maria Deak, Graham B. Bloomberg||, Dario R. Alessi, and Daan M. F. van Aalten, Supported by a Wellcome Trust Senior Research Fellowship and the EMBO Young Investigator Programme**

From the Division of Biological Chemistry and Molecular Microbiology, School of Life Sciences, University of Dundee, DD1 5EH, Scotland, the MRC Protein Phosphorylation Unit, School of Life Sciences, MSI/WTB Complex, University of Dundee, DD1 5EH, Scotland, and the ^||Department of Biochemistry, School of Medical Science, University of Bristol, Bristol BS8 1TD, United Kingdom

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 Å 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.

Received for publication, October 28, 2004 , and in revised form, December 6, 2004.

The atomic coordinates and structure factors (code 1WCH) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported in part by grants from the Association for International Cancer Research (to D. R. A.), Diabetes UK (to D. R. A. and D. M. F. v. A.), the Medical Research Council (to D. R. A.), the Moffat Charitable Trust (to D. R. A.), and the pharmaceutical companies supporting the Division of Signal Transduction Therapy (Astra-Zeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck & Co. Inc, Merck KGaA, and Pfizer). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by a Diabetes UK studentship.

^** To whom correspondence should be addressed. Fax: 44-1382-345764; E-mail: dava{at}davapc1.bioch.dundee.ac.uk.

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