title: Zinc ions modulate protein tyrosine phosphatase 1B activity.
abstract: Protein tyrosine phosphatases (PTPs) are key enzymes in cellular regulation. The 107 human PTPs are regulated by redox signalling, phosphorylation, dimerisation, and proteolysis. Recent findings of very strong inhibition of some PTPs by zinc ions at concentrations relevant in a cellular environment suggest yet another mechanism of regulation. One of the most extensively investigated PTPs is PTP1B (PTPN1). It regulates the insulin and leptin signalling pathway and is implicated in cancer and obesity/diabetes. The development of novel assay conditions to investigate zinc inhibition of PTP1B provides estimates of about 5.6 nM affinity for inhibitory zinc(II) ions. Analysis of three PTP1B 3D structures (PDB id: 2CM2, 3I80 and 1A5Y) identified putative zinc binding sites and supports the kinetic studies in suggesting an inhibitory zinc only in the closed and cysteinyl-phosphate intermediate forms of the enzyme. These observations gain significance with regard to recent findings of regulatory roles of zinc ions released from the endoplasmic reticulum.
authors.affiliation: King's College London, Metal Metabolism Group, Division of Diabetes and Nutritional Sciences, School of Medicine, London, SE1 9NH, UK. elisa.bellomo@kcl.ac.uk.
authors.forename: Elisa
authors.initials: E
authors.lastname: Bellomo
authors.forename: Alberto
authors.initials: A
authors.lastname: Massarotti
authors.forename: Christer
authors.initials: C
authors.lastname: Hogstrand
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maret
mesh_terms: D001665:Binding Sites; D004492:Edetic Acid / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011972:Receptor, Insulin / Q000187:drug effects; D054411:Receptors, Leptin / Q000187:drug effects; D015032:Zinc / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D054411:Receptors, Leptin; D004492:Edetic Acid; D011972:Receptor, Insulin; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D015032:Zinc