title: Oxidative stress-induced oligomerization inhibits the activity of the non-receptor tyrosine phosphatase STEP61.
abstract: The neuron-specific tyrosine phosphatase STriatal Enriched Phosphatase (STEP) is emerging as an important mediator of glutamatergic transmission in the brain. STEP is also thought to be involved in the etiology of neurodegenerative disorders that are linked to oxidative stress such as Alzheimer's disease and cerebral ischemia. However, the mechanism by which oxidative stress can modulate STEP activity is still unclear. In this study, we have investigated whether dimerization may play a role in regulating the activity of STEP. Our findings show that STEP(61), the membrane associated isoform, can undergo homodimerization under basal conditions in neurons. Dimerization of STEP(61) involves intermolecular disulfide bond formation between two cysteine residues (Cys 65 and Cys 76 respectively) present in the hydrophobic region at the N-terminus specific to STEP(61). Oxidative stress induced by hydrogen peroxide leads to a significant increase in the formation of dimers and higher-order oligomers of STEP(61). Using two substrates, para-nitrophenylphosphate and extracellular-regulated kinase MAPK we further demonstrate that oligomerization leads to a significant reduction in its enzymatic activity.
authors.affiliation: Department of Neurology, University of New Mexico Health Sciences Center, 1 University of New Mexico, Albuquerque, New Mexico 87131, USA.
authors.forename: Ishani
authors.initials: I
authors.lastname: Deb
authors.forename: Ranjana
authors.initials: R
authors.lastname: Poddar
authors.forename: Surojit
authors.initials: S
authors.lastname: Paul
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003545:Cysteine / Q000378:metabolism; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047468:Immunoprecipitation / Q000379:methods; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009596:Nitrophenols / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection / Q000379:methods
chemical_list: D009596:Nitrophenols; D009943:Organophosphorus Compounds; C008644:nitrophenylphosphate; D006861:Hydrogen Peroxide; D020929:Mitogen-Activated Protein Kinase Kinases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D003545:Cysteine