Comparative modeling of the phosphatase and kinase domains of protein tyrosine phosphatase and insulin receptor kinase from Drosophila melanogaster (DPTP61fm), and a computational study of their mutual interactions

2002 ◽  
Vol 80 (2) ◽  
pp. 225-239 ◽  
Author(s):  
Sanchita Hati ◽  
Sudeep Bhattacharyya ◽  
James V Price ◽  
Alan S Tracey
Keyword(s):  
Hydrogen Bonding ◽  
Drosophila Melanogaster ◽  
Insulin Receptor ◽  
Protein Tyrosine Phosphatase ◽  
Computational Study ◽  
Tyrosine Phosphatase ◽  
Receptor Kinase ◽  
Protein Tyrosine ◽  
Insulin Receptor Kinase ◽  
High Degree

The components and functions of the insulin receptor kinase signaling pathway have been conserved in a broad range of Metazoa ranging from mammals to insects and nematodes. There is a high degree of sequence homology and functional similarity between the human insulin receptor kinase (IRK) and the drosophila (Drosophila melanogaster) form (DIRK) of this enzyme. Similarly, a high degree of homology exists between human protein tyrosine phosphatase 1B (PTP1B) (which directly regulates IRK) and its drosophila counterpart DPTP61F (DPTP). However, genetic and biochemical studies have yet to demonstrate that DPTP61F acts in the DIRK pathway. Comparative structural modeling techniques using the known structures of human IRK and PTP1B as templates have yielded structures for the drosophila enzymes. The derived structures confirm that there is a high level of structural conservation at the tertiary level. Association of the DIRK and DPTP enzymes with each other was then investigated with a view to ascertaining whether DIRK might be a substrate of the DPTP. Evaluation of the interaction surfaces, including hydrophobic patch, shape, hydrogen bonding, and electrostatic compatibility, strongly suggested that the drosophila insulin receptor is a substrate of the DPTP. The interaction surfaces of the human and drosophila enzymes are structurally similar, although changes in critical residues modify possible electrostatic and hydrogen-bonding interactions. This suggests that in the mixed systems, DPTP–IRK or PTP1B–DIRK, the kinase domain will be a comparatively poor substrate for phosphatase activity when compared with the native systems.Key words: protein tyrosine phosphatase, insulin receptor kinase, Drosophila melanogaster, comparative protein modeling, surface topology, interaction zone.

scholarly journals Elevated protein tyrosine phosphatase activity and increased membrane viscosity are associated with impaired activation of the insulin receptor kinase in old rats

1994 ◽  
Vol 298 (2) ◽  
pp. 443-450 ◽  
Author(s):  
O Nadiv ◽  
M Shinitzky ◽  
H Manu ◽  
D Hecht ◽  
C T Roberts ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Receptor ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Receptor Kinase ◽  
Membrane Viscosity ◽  
Liver Membranes ◽  
Old Rats ◽  
Insulin Receptor Kinase

Insulin resistance is very common in the elderly, and may be associated with glucose intolerance or frank diabetes. In previous studies we demonstrated that insulin resistance in old Wistar rats is associated with decreased autophosphorylation and activation of the hepatic insulin receptor kinase (IRK) in vivo. We now show that this defect can be reproduced in vitro, where the extent of insulin-induced activation of IRK in liver membranes of old rats was decreased by approximately 50% compared with young controls. The defect could be largely abolished after solubilization of the membranes with Triton X-100. We also show that: (a) the viscosity of membranes from the old rats was significantly (P < 0.001, n = 4) higher (by 15%) compared with young controls; (b) incubation of plasma membranes from old animals with lecithin liposomes, which lowered their cholesterol levels, partially abolished the defect in IRK activation; and (c) Triton extracts of liver membranes prepared from old rats did not interfere with the activation of IRK derived from young controls. Additionally, non-membrane components did contribute to the development of this defect. We observed a significant (approximately 30%) (P < 0.001, n = 18) elevation of cytosolic protein tyrosine phosphatase (PTP) activity directed against the beta subunit of the insulin receptor in livers of old rats. No such elevation of PTP activity could be demonstrated with synthetic substrates. Our findings are consistent with a model in which increased membrane viscosity as well as enhancement of a cytosolic PTP activity both markedly inhibit the activation in vivo of the hepatic IRK in old animals.

Potential Inhibitors of Protein Tyrosine Phosphatase (PTP1B) Enzyme: Promising Target for Type-II Diabetes Mellitus

2020 ◽  
Vol 20 (29) ◽  
pp. 2692-2707
Author(s):  
Sisir Nandi ◽  
Mridula Saxena
Keyword(s):  
Insulin Receptor ◽  
Protein Tyrosine Phosphatase ◽  
Type Ii Diabetes ◽  
Tyrosine Phosphatase ◽  
Type Ii Diabetes Mellitus ◽  
Type Ii ◽  
Insulin Effect ◽  
Protein Tyrosine ◽  
Ptp1b Inhibitors ◽  
Insulin Dependent Diabetic

Background: There has been growing interest in the development of highly potent and selective protein tyrosine phosphatase (PTP1B) inhibitors for the past 2-3 decades. Though most PTPs share a common active site motif, the interest in selective inhibitors, particularly against PTP1B is increasing to discover new chemical entities as antidiabetic agents. In the current paradigm to find potent and selective PTP1B inhibitors, which is currently considered as one of the best validated biological targets for non-insulin-dependent diabetic and obese individuals, resistance to insulin due to decreased sensitivity of the insulin receptor is a pathological factor and is also genetically linked, causing type II diabetes. Objectives: Insulin receptor sensitization is performed by a signal transduction mechanism via a selective protein tyrosine phosphatase (PTP1B). After the interaction of insulin with its receptor, autophosphorylation of the intracellular part of the receptor takes place, turning it into an active kinase (sensitization). PTP1B is involved in the desensitization of the receptor by dephosphorylation. PTP1b inhibitors delay the receptor desensitization, prolonging insulin effect and making PTP1B as a drug target for the treatment of diabetes II. Therefore, it has become a major target for the discovery of potent drugs for the treatment of type II diabetes and obesity. An attempt has been made in the present study to discuss the latest design and discovery of protein tyrosine phosphatase (PTP1B) inhibitors. Methods: Many PTP1B inhibitors such as diaminopyrroloquinazoline, triazines, pyrimido triazine derivatives, 2-(benzylamino)-1-phenylethanol, urea, acetamides and piperazinylpropanols, phenylsulphonamides and phenylcarboxamide, benzamido, arylcarboxylic acid derivatives, arylsupfonyl derivatives, thiazoles, isothiozolidiones and thiazolodinones have been discussed, citing the disease mechanisms. Results: The reader will gain an overview of the structure and biological activity of recently developed PTPs inhibitors. Conclusion: The co-crystallized ligands and the screened inhibitors could be used as a template for the further design of potent congeners.

scholarly journals Regulation of Insulin Receptor Signaling by the Protein Tyrosine Phosphatase TCPTP

2003 ◽  
Vol 23 (6) ◽  
pp. 2096-2108 ◽  
Author(s):  
Sandra Galic ◽  
Manuela Klingler-Hoffmann ◽  
Michelle T. Fodero-Tavoletti ◽  
Michelle A. Puryer ◽  
Tzu-Ching Meng ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Protein Tyrosine Phosphatase ◽  
Tyrosine Phosphatase ◽  
Cell Periphery ◽  
Β Subunit ◽  
Insulin Stimulation ◽  
Protein Tyrosine ◽  
Akt Activation ◽  
Insulin Receptor Signaling

ABSTRACT The human protein tyrosine phosphatase TCPTP exists as two forms: an endoplasmic reticulum-targeted 48-kDa form (TC48) and a nuclear 45-kDa form (TC45). Although targeted to the nucleus, TC45 can exit in response to specific stimuli to dephosphorylate cytoplasmic substrates. In this study, we investigated the downregulation of insulin receptor (IR) signaling by TCPTP. In response to insulin stimulation, the TC48-D182A and TC45-D182A “substrate-trapping” mutants formed stable complexes with the endogenous tyrosine-phosphorylated IR β-subunit in 293 cells. Moreover, in response to insulin stimulation, the TC45-D182A mutant accumulated in the cytoplasm of cells overexpressing the IR and in part colocalized with the IR β-subunit at the cell periphery. These results indicate that the IR may serve as a cellular substrate for both TC48 and TC45. In immortalized TCPTP−/− murine embryo fibroblasts, insulin-induced IR β-subunit tyrosine phosphorylation and protein kinase PKB/Akt activation were enhanced relative to the values in TCPTP+/+ cells. Importantly, the expression of TC45 or TC48 to physiological levels suppressed the enhanced insulin-induced signaling in TCPTP−/− cells. These results indicate that the differentially localized variants of TCPTP may dephosphorylate the IR and downregulate insulin-induced signaling in vivo.

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