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Phosphatases

Phosphatases. Structure & Biochemistry PTP PPP PPM. Protein Tyrosine Phosphatases. Parallel active and inactive phosphatase domains. PTP. Diverse family Receptor/Nonreceptor Tyrosine specific/Dual specificity MAPK phosphatases Catalytic cysteine residue Reactive sulfur Oxidizable.

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Phosphatases

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  1. Phosphatases • Structure & Biochemistry • PTP • PPP • PPM

  2. Protein Tyrosine Phosphatases Parallel active and inactive phosphatase domains

  3. PTP • Diverse family • Receptor/Nonreceptor • Tyrosine specific/Dual specificity • MAPK phosphatases • Catalytic cysteine residue • Reactive sulfur • Oxidizable Cysteine PDB: 3eu0

  4. PTP regulation • Regulatory domains • Targeting to compartments or proteins • Allosteric sensors • Autoinhibition • Proteolysis • Phosphorylation • Oxidation • Diversity • Overlapping substrates among members • Opposing functions – MKPs, SHPs

  5. Cell adhesion • IntegrinFAKp130cascrkracadhesion • PTP-PEST • Paxillin binding • Targets FAK, p130cas, others • Focal adhesion turnover • Constitutive • Negative feedback Mitra, et al 2005

  6. Yersinia • Tuberculosis • Bubonic plague • YopH PTP • IgGFcyR (RTK) Fyn Syk dynamin phagocytosis • YopH--|FyB • Highest activity PTP • Many targets related to phagocytosis • Blocks inflammatory phagocytosis of bacteria Yersinia Pestis colony Rocky Mountain Laboratories, NIAID

  7. Ser/Thr phosphatases • Common ancestor, common catalytic domain • Regulation by binding partners • Specificity • Localization • Activity • Catalytic metals • Fe/Mn • Fe/Zn • Oxidizable • PP1 • Glycogen metabolism (GS) • Cell cycle progression • Glutaminergic transmission (AMPA, NMDA) Catalytic Mn++ PP1a PDB: 1FJM

  8. PPP Phosphatases • PP2A • Cell cycle & division • Cyclin G partner • Suppression of migration • PP2B/calcineurin • Calcium dependent • Immunomodulation • NFAT

  9. PPP regulation of glycogen breakdown • adrenaline  β-AR AC  PKA • PKAPhK phosphorylaseglycogen breakdown into glucose • PhK--|GSsynthesis of glycogen from glucose • PKA--|GM-PP1--|phosphorylase • GM-PP1GS • GM glycogen targeting subunit of PP1 • GM binds ER, near muscle glycogen stores • GM binds PP1; PP1 near glycogen inactivates phosphorylase, activates GS • Phospho-GM does not bind PP1 • Phosphorylation of PP1 itself will also decrease activity

  10. PPM Phosphatases • PP2C relatives • Mn2+/Mn2+ catalytic center • Transcriptional regulation • Eg: wip1 • p53wip1--|p38p53apoptosis • Negative feedback on cell death subsequent to DNA damage, UV stress…

  11. t t t t t t t t Long term plasticity of glutaminergic synapses Persistent low-/in-activity High frequency burst Pre-synaptic firing (glutamate release) Long term potentiation Long term depression Post-synaptic EPSP (Na influx through AMPA) Post-synaptic Calcium (Ca influx through NMDA) Post-synaptic AMPA phosphorylation

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