Abstract
RECEPTOR-LIKE protein-tyrosine phosphatases (RPTPs), like their non-receptor counterparts, regulate the level of phosphotyrosine-containing proteins derived from the action of protein-tyrosine kineses1. RPTPs are type-I integral membrane proteins which contain one or two catalytic domains in their cytoplasmic region2. It is not known whether extracellular ligands regulate the activity of RPTPs. Here we describe the crystal structure of the membrane-proximal catalytic domain (D1) of a typical RPTP, murine RPTPα. Significant structural deviations from the PTP1B fold reside within the amino-terminal helix–turn–helix segment of RPTPαD1 (residues 214 to 242) and a distinctive two-stranded β-sheet formed between residues 211–213 and 458–461. The turn of the N-terminal segment inserts into the active site of a dyad-related D1 monomer. On the basis of two independent crystal structures, sequence alignments, and the reported biological activity of EGF receptor/CD45 chimaeras3, we propose that dimerization and active-site blockage is a physiologically important mechanism for downregulating the catalytic activity of RPTPα and other RPTPs.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hunter, T. Cell 80, 225–236 (1995).
Mourey, R. J. & Dixon, J. E. Curr. Opin. Genet. Dev. 4, 31–39 (1994).
Desai, D. M., Sap, J., Schlessinger, J. & Weiss, A. Cell 73, 541–554 (1993).
Peles, E. et al. Cell 82, 251–260 (1995).
den Hertog, J., Tracy, S. & Hunter, T. EMBO J. 13, 3020–3032 (1994).
Janin, J. & Chothia, C. J. biol. Chem. 265, 16027–16030 (1990).
Schmitz, K. S. An Introduction to Dynamic Light Scattering by Macromolecules (Academic, Boston, MA, 1990).
Barford, D., Flint, A. J. & Tonks, N. K. Science 263, 1397–1404 (1994).
Stuckey, J. A. et al. Nature 370, 571–575 (1994).
Schubert, H. L., Fauman, E. B., Stuckey, J. A., Dixon, J. E. & Saper, M. Protein Sci. 4, 1904–1913 (1995).
Jia, Z., Barford, D., Flint, A. J. & Tonks, N. K. Science 268, 1754–1758 (1995).
Zhang, Z. Y., Wang, Y. & Dixon, J. E. Proc. natn. Acad. Sci. U.S.A. 91, 1624–1627 (1994).
Tracy, S., van der Geer, P. & Hunter, T. J. biol. Chem. 270, 10587–10594 (1995).
Takeda, A., Wu, J. J. & Maizel, A. L. J. biol. Chem. 267, 16651–16659 (1992).
Otwinowski, Z. Data Collection and Processing (SERC Daresbury Laboratory, Warrington, 1993).
Collaborative Computing Project No. 4 Acta crystallogr. D50, 760–763 (1994).
Navaza, J. Acta crystallogr. A50, 157–163 (1994).
Upson, C. et al. IEEE Comput. Graphics Appli. 9(4), 30–42 (1989).
Wild, D. L., Tucker, P. A. & Choe, S. J. molec. Graphics 13, 291–298 (1995).
Jones, T. A., Zou, J. Y., Cowan, S. W. & Kjeldgaard, M. Acta crystallogr. A47, 110–119 (1991).
Brunger, A. T. X-PLOR, Version 3.1. (Yale Univ. Press, New Haven, CT 1992).
Lamzin, V. S. & Wilson, K. S. Acta crystallogr. D49, 127–149 (1993).
Laskowski, R. A., MacArthur, M. W., Moss, D. S. & Thornton, J. M. J. appl. Crystallogr. 26, 283–291 (1993).
Huang, C. C., Pettersen, E. F., Klein, T. E. & Langridge, R. J. molec. Graphics 9, 230–236 (1991).
Ferrin, T. E., Huang, C. C., Jarvis, L. E. & Langridge, R. J. molec. Graphics 6, 13–27 (1988).
Evans, S. V. J. molec. Graphics 11, 134–138 (1993).
Goldstein, B. J. Phosphoprotein Phosphatases 1: Tyrosine Phosphatases (Academic, London, 1995).
Sap, J., D'Eustachio, P., Givol, D. & Schlessinger, J. Proc. natn. Acad. Sci. U.S.A. 87, 6112–6116 (1990).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Bilwes, A., den Hertog, J., Hunter, T. et al. Structural basis for inhibition of receptor protein-tyrosine phosphatase-α by dimerization. Nature 382, 555–559 (1996). https://doi.org/10.1038/382555a0
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/382555a0
This article is cited by
-
Structural basis of liprin-α-promoted LAR-RPTP clustering for modulation of phosphatase activity
Nature Communications (2020)
-
Hepatic protein tyrosine phosphatase receptor gamma links obesity-induced inflammation to insulin resistance
Nature Communications (2017)
-
Protein Tyrosine Phosphatase Inhibition Prevents Experimental Cerebral Malaria by Precluding CXCR3 Expression on T Cells
Scientific Reports (2017)
-
Structure of the Catalytic Domain of Protein Tyrosine Phosphatase Sigma in the Sulfenic Acid Form
Molecules and Cells (2013)
-
Protein Tyrosine Phosphatase σ in Proteoglycan-Mediated Neural Regeneration Regulation
Molecular Neurobiology (2013)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.