Download Phosphatases - Georgia Institute of Technology

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
Cysteine
PDB: 3eu0
PTP regulation
• Regulatory domains
– Targeting to compartments or proteins
– Allosteric sensors
– Autoinhibition
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Proteolysis
Phosphorylation
Oxidation
Diversity
– Overlapping substrates among members
– Opposing functions – MKPs, SHPs
Cell adhesion
• IntegrinFAKp130cascrkracad
hesion
• PTP-PEST
– Paxillin binding
– Targets FAK, p130cas, others
– Focal adhesion turnover
• Constitutive
• Negative feedback
Mitra, et al 2005
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
Ser/Thr phosphatases
• Common ancestor, common catalytic domain
• Regulation by binding partners
– Specificity
– Localization
– Activity
Catalytic Mn++
PP1a
• Catalytic metals
– Fe/Mn
– Fe/Zn
– Oxidizable
• PP1
– Glycogen metabolism (GS)
– Cell cycle progression
– Glutaminergic transmission (AMPA, NMDA)
PDB: 1FJM
PPP Phosphatases
• PP2A
– Cell cycle & division
– Cyclin G partner
– Suppression of migration
• PP2B/calcineurin
– Calcium dependent
– Immunomodulation
– NFAT
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
PPM Phosphatases
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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…
Long term plasticity of glutaminergic synapses
Persistent low-/in-activity
High frequency burst
Pre-synaptic firing
(glutamate release)
t
Long term potentiation
Long term depression
t
Post-synaptic EPSP
t
(Na influx through AMPA)
t
Post-synaptic Calcium
t
(Ca influx through NMDA)
t
Post-synaptic AMPA
phosphorylation
t
t