scholarly journals Structural basis for the function and regulation of the receptor protein tyrosine phosphatase CD45

2005 ◽  
Vol 201 (3) ◽  
pp. 441-452 ◽  
Author(s):  
Hyun-Joo Nam ◽  
Florence Poy ◽  
Haruo Saito ◽  
Christin A. Frederick
Keyword(s):  
Crystal Structure ◽  
Protein Tyrosine Phosphatase ◽  
Active Site ◽  
Active Sites ◽  
Hydrophobic Interactions ◽  
Tyrosine Phosphatase ◽  
Receptor Protein ◽  
Structural Basis ◽  
Salt Bridges ◽  
Protein Tyrosine

CD45 is the prototypic member of transmembrane receptor-like protein tyrosine phosphatases (RPTPs) and has essential roles in immune functions. The cytoplasmic region of CD45, like many other RPTPs, contains two homologous protein tyrosine phosphatase domains, active domain 1 (D1) and catalytically impaired domain 2 (D2). Here, we report crystal structure of the cytoplasmic D1D2 segment of human CD45 in native and phosphotyrosyl peptide-bound forms. The tertiary structures of D1 and D2 are very similar, but doubly phosphorylated CD3ζ immunoreceptor tyrosine-based activation motif peptide binds only the D1 active site. The D2 “active site” deviates from the other active sites significantly to the extent that excludes any possibility of catalytic activity. The relative orientation of D1 and D2 is very similar to that observed in leukocyte common antigen–related protein with both active sites in an open conformation and is restrained through an extensive network of hydrophobic interactions, hydrogen bonds, and salt bridges. This crystal structure is incompatible with the wedge model previously suggested for CD45 regulation.

scholarly journals The crystal structure of human receptor protein tyrosine phosphatase κ phosphatase domain 1

2006 ◽  
Vol 15 (6) ◽  
pp. 1500-1505 ◽  
Author(s):  
Jeyanthy Eswaran ◽  
Judit É. Debreczeni ◽  
Emma Longman ◽  
Alastair J. Barr ◽  
Stefan Knapp
Keyword(s):  
Crystal Structure ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Receptor Protein ◽  
Phosphatase Domain ◽  
Protein Tyrosine ◽  
Receptor Protein Tyrosine Phosphatase ◽  
Human Receptor

scholarly journals A novel strategy for the development of selective active-site inhibitors of the protein tyrosine phosphatase-like proteins islet-cell antigen 512 (IA-2) and phogrin (IA-2beta)

2003 ◽  
Vol 373 (2) ◽  
pp. 393-401 ◽  
Author(s):  
Paul G. DRAKE ◽  
Günther H. PETERS ◽  
Henrik Sune ANDERSEN ◽  
Wiljan HENDRIKS ◽  
Niels Peter H. MØLLER
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Active Site ◽  
Islet Cell ◽  
Tyrosine Phosphatase ◽  
Receptor Protein ◽  
Wild Type ◽  
Protein Tyrosine ◽  
Cell Antigen ◽  
Type Ia ◽  
Novel Strategy

Islet-cell antigen 512 (IA-2) and phogrin (IA-2β) are atypical members of the receptor protein tyrosine phosphatase (PTP) family that are characterized by a lack of activity against conventional PTP substrates. The physiological role(s) of these proteins remain poorly defined, although recent studies indicate that IA-2 may be involved in granule trafficking and exocytosis. To further understand their function, we have embarked upon developing low-molecular-mass inhibitors of IA-2 and IA-2β. Previously, we have shown that a general PTP inhibitor, 2-(oxalylamino)benzoic acid (OBA), can be developed into highly selective and potent inhibitors of PTP1B. However, since wild-type IA-2 and IA-2β lack conventional PTP activity, a novel strategy was designed whereby catalytically active species were generated by ‘back-mutating’ key non-consensus catalytic region residues to those of PTP1B. These mutants were then used as tools with which to test the potency and selectivity of OBA and a variety of its derivatives. Catalytically competent IA-2 and IA-2β species were generated by ‘back-mutation’ of only three key residues (equivalent to Tyr46, Asp181 and Ala217 using the human PTP1B numbering) to those of PTP1B. Importantly, enzyme kinetic analyses indicated that the overall fold of both mutant and wild-type IA-2 and IA-2β was similar to that of classic PTPs. In particular, one derivative of OBA, namely 7-(1,1-dioxo-1H-benzo[d]isothiazol-3-yloxymethyl)-2-(oxalylamino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3 -carboxylic acid (‘Compound 6’ shown in the main paper), which inhibited IA-2β(S762Y/Y898P/D933A) (IA-2β in which Ser762 has been mutated to tyrosine, Tyr898 to proline, and Asp933 to alanine) with a Ki value of ≈8 μM, appeared ideal for future lead optimization. Thus molecular modelling of this classical, competitive inhibitor in the catalytic site of wild-type IA-2β identified two residues (Ser762 and Asp933) that offer the possibility for unique interaction with an appropriately modified ‘Compound 6’. Such a compound has the potential to be a highly selective and potent active-site inhibitor of wild-type IA-2β.

Structural basis for inhibition of receptor protein-tyrosine phosphatase-α by dimerization

Nature ◽  
1996 ◽  
Vol 382 (6591) ◽  
pp. 555-559 ◽  
Author(s):  
Alexandrine M. Bilwes ◽  
Jeroen den Hertog ◽  
Tony Hunter ◽  
Joseph P. Noel
Keyword(s):  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Receptor Protein ◽  
Structural Basis ◽  
Protein Tyrosine ◽  
Receptor Protein Tyrosine Phosphatase

scholarly journals Extracellular Matrix Remodeling in the Retina and Optic Nerve of a Novel Glaucoma Mouse Model

Biology ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 169
Author(s):  
Jacqueline Reinhard ◽  
Susanne Wiemann ◽  
Sebastian Hildebrandt ◽  
Andreas Faissner
Keyword(s):  
Extracellular Matrix ◽  
Optic Nerve ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Nerve Fibers ◽  
Receptor Protein ◽  
Mrna Levels ◽  
Protein Tyrosine ◽  
Tenascin C ◽  
Iop Elevation

Glaucoma is a neurodegenerative disease that is characterized by the loss of retinal ganglion cells (RGC) and optic nerve fibers. Increased age and intraocular pressure (IOP) elevation are the main risk factors for developing glaucoma. Mice that are heterozygous (HET) for the mega-karyocyte protein tyrosine phosphatase 2 (PTP-Meg2) show chronic and progressive IOP elevation, severe RGCs loss, and optic nerve damage, and represent a valuable model for IOP-dependent primary open-angle glaucoma (POAG). Previously, evidence accumulated suggesting that glaucomatous neurodegeneration is associated with the extensive remodeling of extracellular matrix (ECM) molecules. Unfortunately, little is known about the exact ECM changes in the glaucomatous retina and optic nerve. Hence, the goal of the present study was to comparatively explore ECM alterations in glaucomatous PTP-Meg2 HET and control wild type (WT) mice. Due to their potential relevance in glaucomatous neurodegeneration, we specifically analyzed the expression pattern of the ECM glycoproteins fibronectin, laminin, tenascin-C, and tenascin-R as well as the proteoglycans aggrecan, brevican, and members of the receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) family. The analyses were carried out in the retina and optic nerve of glaucomatous PTP-Meg2 HET and WT mice using quantitative real-time PCR (RT-qPCR), immunohistochemistry, and Western blot. Interestingly, we observed increased fibronectin and laminin levels in the glaucomatous HET retina and optic nerve compared to the WT group. RT-qPCR analyses of the laminins α4, β2 and γ3 showed an altered isoform-specific regulation in the HET retina and optic nerve. In addition, an upregulation of tenascin-C and its interaction partner RPTPβ/ζ/phosphacan was found in glaucomatous tissue. However, comparable protein and mRNA levels for tenascin-R as well as aggrecan and brevican were observed in both groups. Overall, our study showed a remodeling of various ECM components in the glaucomatous retina and optic nerve of PTP-Meg2 HET mice. This dysregulation could be responsible for pathological processes such as neovascularization, inflammation, and reactive gliosis in glaucomatous neurodegeneration.

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