Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 31 May 1996:
Vol. 272. no. 5266, pp. 1328 - 1331
DOI: 10.1126/science.272.5266.1328
Prev | Table of Contents | Next

Reports

Crystal Structure of the Dual Specificity Protein Phosphatase VHR

Jirundon Yuvaniyama, John M. Denu, Jack E. Dixon, Mark A. Saper *

Dual specificity protein phosphatases (DSPs) regulate mitogenic signal transduction and control the cell cycle. Here, the crystal structure of a human DSP, vaccinia H1-related phosphatase (or VHR), was determined at 2.1 angstrom resolution. A shallow active site pocket in VHR allows for the hydrolysis of phosphorylated serine, threonine, or tyrosine protein residues, whereas the deeper active site of protein tyrosine phosphatases (PTPs) restricts substrate specificity to only phosphotyrosine. Positively charged crevices near the active site may explain the enzyme's preference for substrates with two phosphorylated residues. The VHR structure defines a conserved structural scaffold for both DSPs and PTPs. A ``recognition region,'' connecting helix alpha 1 to strand beta 1, may determine differences in substrate specificity between VHR, the PTPs, and other DSPs.

J. Yuvaniyama and M. A. Saper, Biophysics Research Division and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109-1055, USA.
J. M. Denu and J. E. Dixon, Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109-0606, USA.
* To whom correspondence should be addressed. E-mail: saper{at}umich.edu


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Physiological Signaling Specificity by Protein Tyrosine Phosphatases.
M. Soulsby and A. M. Bennett (2009)
Physiology 24, 281-289
   Abstract »    Full Text »    PDF »
Dimeric Quaternary Structure of the Prototypical Dual Specificity Phosphatase VH1.
A. C. Koksal, J. D. Nardozzi, and G. Cingolani (2009)
J. Biol. Chem. 284, 10129-10137
   Abstract »    Full Text »    PDF »
Molecular Dissection of the Mechanisms of Substrate Recognition and F-actin-mediated Activation of Cofilin-phosphatase Slingshot-1.
S. Kurita, Y. Watanabe, E. Gunji, K. Ohashi, and K. Mizuno (2008)
J. Biol. Chem. 283, 32542-32552
   Abstract »    Full Text »    PDF »
Regulation of MAPK Phosphatase 1 (AtMKP1) by Calmodulin in Arabidopsis.
K. Lee, E. H. Song, H. S. Kim, J. H. Yoo, H. J. Han, M. S. Jung, S. M. Lee, K. E. Kim, M. C. Kim, M. J. Cho, et al. (2008)
J. Biol. Chem. 283, 23581-23588
   Abstract »    Full Text »    PDF »
Structure of Human Dual Specificity Protein Phosphatase 23, VHZ, Enzyme-Substrate/Product Complex.
R. Agarwal, S. K. Burley, and S. Swaminathan (2008)
J. Biol. Chem. 283, 8946-8953
   Abstract »    Full Text »    PDF »
The phosphatase laforin crosses evolutionary boundaries and links carbohydrate metabolism to neuronal disease.
M. S. Gentry, R. H. Dowen III, C. A. Worby, S. Mattoo, J. R. Ecker, and J. E. Dixon (2007)
J. Cell Biol. 178, 477-488
   Abstract »    Full Text »    PDF »
Solution Structure of a Low-Molecular-Weight Protein Tyrosine Phosphatase from Bacillus subtilis.
H. Xu, B. Xia, and C. Jin (2006)
J. Bacteriol. 188, 1509-1517
   Abstract »    Full Text »    PDF »
Molecular basis for substrate recognition by MTMR2, a myotubularin family phosphoinositide phosphatase.
M. J. Begley, G. S. Taylor, M. A. Brock, P. Ghosh, V. L. Woods, and J. E. Dixon (2006)
PNAS 103, 927-932
   Abstract »    Full Text »    PDF »
PRL phosphatases as potential molecular targets in cancer.
B. J. Stephens, H. Han, V. Gokhale, and D. D. Von Hoff (2005)
Mol. Cancer Ther. 4, 1653-1661
   Abstract »    Full Text »    PDF »
From The Cover: Insights into Lafora disease: Malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin.
M. S. Gentry, C. A. Worby, and J. E. Dixon (2005)
PNAS 102, 8501-8506
   Abstract »    Full Text »    PDF »
Crystal Structure of Baculovirus RNA Triphosphatase Complexed with Phosphate.
A. Changela, A. Martins, S. Shuman, and A. Mondragon (2005)
J. Biol. Chem. 280, 17848-17856
   Abstract »    Full Text »    PDF »
Crystal Structure of Low-Molecular-Weight Protein Tyrosine Phosphatase from Mycobacterium tuberculosis at 1.9-A Resolution.
C. Madhurantakam, E. Rajakumara, P. A. Mazumdar, B. Saha, D. Mitra, H. G. Wiker, R. Sankaranarayanan, and A. K. Das (2005)
J. Bacteriol. 187, 2175-2181
   Abstract »    Full Text »    PDF »
Crystal structure of the protein histidine phosphatase SixA in the multistep His-Asp phosphorelay.
K. Hamada, M. Kato, T. Shimizu, K. Ihara, T. Mizuno, and T. Hakoshima (2005)
Genes Cells 10, 1-11
   Abstract »    Full Text »    PDF »
The Minimal Essential Core of a Cysteine-based Protein-tyrosine Phosphatase Revealed by a Novel 16-kDa VH1-like Phosphatase, VHZ.
A. Alonso, S. Burkhalter, J. Sasin, L. Tautz, J. Bogetz, H. Huynh, M. C. D. Bremer, L. J. Holsinger, A. Godzik, and T. Mustelin (2004)
J. Biol. Chem. 279, 35768-35774
   Abstract »    Full Text »    PDF »
VHY, a Novel Myristoylated Testis-restricted Dual Specificity Protein Phosphatase Related to VHX.
A. Alonso, S. Narisawa, J. Bogetz, L. Tautz, R. Hadzic, H. Huynh, S. Williams, A. Gjorloff-Wingren, M. C. D. Bremer, L. J. Holsinger, et al. (2004)
J. Biol. Chem. 279, 32586-32591
   Abstract »    Full Text »    PDF »
A Semidominant Mutation in an Arabidopsis Mitogen-Activated Protein Kinase Phosphatase-Like Gene Compromises Cortical Microtubule Organization.
K. Naoi and T. Hashimoto (2004)
PLANT CELL 16, 1841-1853
   Abstract »    Full Text »    PDF »
Evolution of the Multifunctional Protein Tyrosine Phosphatase Family.
B. Pils and J. Schultz (2004)
Mol. Biol. Evol. 21, 625-631
   Abstract »    Full Text »    PDF »
Structural Insights into Molecular Function of the Metastasis-associated Phosphatase PRL-3.
G. Kozlov, J. Cheng, E. Ziomek, D. Banville, K. Gehring, and I. Ekiel (2004)
J. Biol. Chem. 279, 11882-11889
   Abstract »    Full Text »    PDF »
IBR5, a Dual-Specificity Phosphatase-Like Protein Modulating Auxin and Abscisic Acid Responsiveness in Arabidopsis.
M. Monroe-Augustus, B. K. Zolman, and B. Bartel (2003)
PLANT CELL 15, 2979-2991
   Abstract »    Full Text »    PDF »
The Catalytic Mechanism of Cdc25A Phosphatase.
D. F. McCain, I. E. Catrina, A. C. Hengge, and Z.-Y. Zhang (2002)
J. Biol. Chem. 277, 11190-11200
   Abstract »    Full Text »    PDF »
Inhibition of T Cell Antigen Receptor Signaling by VHR-related MKPX (VHX), a New Dual Specificity Phosphatase Related to VH1 Related (VHR).
A. Alonso, J. J. Merlo, S. Na, N. Kholod, L. Jaroszewski, A. Kharitonenkov, S. Williams, A. Godzik, J. D. Posada, and T. Mustelin (2002)
J. Biol. Chem. 277, 5524-5528
   Abstract »    Full Text »    PDF »
Activation of the Jnk signaling pathway by a dual-specificity phosphatase, JSP-1.
Y. Shen, R. Luche, B. Wei, M. L. Gordon, C. D. Diltz, and N. K. Tonks (2001)
PNAS 98, 13613-13618
   Abstract »    Full Text »    PDF »
Mechanistic Basis for Catalytic Activation of Mitogen-activated Protein Kinase Phosphatase 3 by Extracellular Signal-regulated Kinase.
C. C. Fjeld, A. E. Rice, Y. Kim, K. R. Gee, and J. M. Denu (2000)
J. Biol. Chem. 275, 6749-6757
   Abstract »    Full Text »    PDF »
Mechanism of Mitogen-activated Protein Kinase Phosphatase-3 Activation by ERK2.
B. Zhou and Z.-Y. Zhang (1999)
J. Biol. Chem. 274, 35526-35534
   Abstract »    Full Text »    PDF »
Extracellular Regulated Kinases (ERK) 1 and ERK2 Are Authentic Substrates for the Dual-specificity Protein-tyrosine Phosphatase VHR. A NOVEL ROLE IN DOWN-REGULATING THE ERK PATHWAY.
J. L. Todd, K. G. Tanner, and J. M. Denu (1999)
J. Biol. Chem. 274, 13271-13280
   Abstract »    Full Text »    PDF »
Molecular Basis for Substrate Specificity of Protein-tyrosine Phosphatase 1B.
M. Sarmiento, Y. Zhao, S. J. Gordon, and Z.-Y. Zhang (1998)
J. Biol. Chem. 273, 26368-26374
   Abstract »    Full Text »    PDF »
Crystal Structure of a Human Low Molecular Weight Phosphotyrosyl Phosphatase. IMPLICATIONS FOR SUBSTRATE SPECIFICITY.
M. Zhang, C. V. Stauffacher, D. Lin, and R. L. Van Etten (1998)
J. Biol. Chem. 273, 21714-21720
   Abstract »    Full Text »    PDF »
Growth stimulation of primary B cell precursors by the anti-phosphatase Sbf1.
I. De Vivo, X. Cui, J. Domen, and M. L. Cleary (1998)
PNAS 95, 9471-9476
   Abstract »    Full Text »    PDF »
RNA Molecules That Bind to and Inhibit the Active Site of a Tyrosine Phosphatase.
S. D. Bell, J. M. Denu, J. E. Dixon, and A. D. Ellington (1998)
J. Biol. Chem. 273, 14309-14314
   Abstract »    Full Text »    PDF »
Suramin Is an Active Site-directed, Reversible, and Tight-binding Inhibitor of Protein-tyrosine Phosphatases.
Y.-L. Zhang, Y.-F. Keng, Y. Zhao, L. Wu, and Z.-Y. Zhang (1998)
J. Biol. Chem. 273, 12281-12287
   Abstract »    Full Text »    PDF »
Molecular Characterization of a Tyrosine-Specific Protein Phosphatase Encoded by a Stress-Responsive Gene in Arabidopsis.
Q. Xu, H.-H. Fu, R. Gupta, and S. Luan (1998)
PLANT CELL 10, 849-858
   Abstract »    Full Text »    PDF »
Visualization of the Cysteinyl-phosphate Intermediate of a Protein-tyrosine Phosphatase by X-ray Crystallography.
A. D. B. Pannifer, A. J. Flint, N. K. Tonks, and D. Barford (1998)
J. Biol. Chem. 273, 10454-10462
   Abstract »    Full Text »    PDF »
The Mitogen-activated Protein Kinase Phosphatase-3 N-terminal Noncatalytic Region Is Responsible for Tight Substrate Binding and Enzymatic Specificity.
M. Muda, A. Theodosiou, C. Gillieron, A. Smith, C. Chabert, M. Camps, U. Boschert, N. Rodrigues, K. Davies, A. Ashworth, et al. (1998)
J. Biol. Chem. 273, 9323-9329
   Abstract »    Full Text »    PDF »
Altering the Nucleophile Specificity of a Protein-tyrosine Phosphatase-catalyzed Reaction. PROBING THE FUNCTION OF THE INVARIANT GLUTAMINE RESIDUES.
Y. Zhao, L. Wu, S. J. Noh, K.-L. Guan, and Z.-Y. Zhang (1998)
J. Biol. Chem. 273, 5484-5492
   Abstract »    Full Text »    PDF »
Growth suppression of glioma cells by PTEN requires a functional phosphatase catalytic domain.
F. B. Furnari, H. Lin, H.-J. S. Huang, and W. K. Cavenee (1997)
PNAS 94, 12479-12484
   Abstract »    Full Text »    PDF »
P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase.
M. P. Myers, J. P. Stolarov, C. Eng, J. Li, S. I. Wang, M. H. Wigler, R. Parsons, and N. K. Tonks (1997)
PNAS 94, 9052-9057
   Abstract »    Full Text »    PDF »
Purification and Kinetic Characterization of the Mitogen-activated Protein Kinase Phosphatase rVH6.
A. M. Wiland, J. M. Denu, R. J. Mourey, and J. E. Dixon (1996)
J. Biol. Chem. 271, 33486-33492
   Abstract »    Full Text »    PDF »
Kinetic Analysis of the Catalytic Domain of Human Cdc25B.
E. B. Gottlin, X. Xu, D. M. Epstein, S. P. Burke, J. W. Eckstein, D. P. Ballou, and J. E. Dixon (1996)
J. Biol. Chem. 271, 27445-27449
   Abstract »    Full Text »    PDF »
Regulation of Dual-specificity Phosphatases M3/6 and hVH5 by Phorbol Esters. ANALYSIS OF A DELTA-LIKE DOMAIN.
T. R. Johnson, J. R. Biggs, S. E. Winbourn, and A. S. Kraft (2000)
J. Biol. Chem. 275, 31755-31762
   Abstract »    Full Text »    PDF »
Inhibitory Role for Dual Specificity Phosphatase VHR in T Cell Antigen Receptor and CD28-induced Erk and Jnk Activation.
A. Alonso, M. Saxena, S. Williams, and T. Mustelin (2001)
J. Biol. Chem. 276, 4766-4771
   Abstract »    Full Text »    PDF »
Mutational and Kinetic Evaluation of Conserved His-123 in Dual Specificity Protein-tyrosine Phosphatase Vaccinia H1-related Phosphatase. PARTICIPATION OF TYR-78 AND THR-73 RESIDUES IN TUNING THE ORIENTATION OF HIS-123.
J.-H. Kim, D. Y. Shin, M.-H. Han, and M.-U. Choi (2001)
J. Biol. Chem. 276, 27568-27574
   Abstract »    Full Text »    PDF »
The Mechanism of Dephosphorylation of Extracellular Signal-regulated Kinase 2 by Mitogen-activated Protein Kinase Phosphatase 3.
Y. Zhao and Z.-Y. Zhang (2001)
J. Biol. Chem. 276, 32382-32391
   Abstract »    Full Text »    PDF »
Discordance between the Binding Affinity of Mitogen-activated Protein Kinase Subfamily Members for MAP Kinase Phosphatase-2 and Their Ability to Activate the Phosphatase Catalytically.
P. Chen, D. Hutter, X. Yang, M. Gorospe, R. J. Davis, and Y. Liu (2001)
J. Biol. Chem. 276, 29440-29449
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)