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Protein phosphatases. Protein phosphatase acting as a reset button for kinases this action is either a) inactivating or b) activating. like for protein kinases, a distinction is made between tyrosine and threonine /serine phosphatases. - PowerPoint PPT Presentation
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Protein phosphatases
Protein phosphatase acting
as a reset button for kinases
this action is eithera) inactivating
orb) activating
like for protein kinases, a distinction is made between tyrosine and threonine/serine phosphatases
As there is always an exception to the rule: certain phosphatases recognize both phosphotyrosine and
phosphothreonine/serine residues
these are the dual specificity phosphatases
serinethreonine
tyrosine
serinethreoninetyrosine
{
{
{
The depth of the catalytic pocket is one of the determinants of phosphoresidue specificity of the protein phosphatase
Serine / threonine phosphatases
Mechanism of action and highly conserved (signature) sequences of serine / threonine protein phosphatases. The catalytic subunits have broad specificity
Specificity of serine/threonine phosphatases is largely determined by association of regulatory subunits that affect subcellular localisation as well
as substrate specificity
The regulatory subunit MYPT1 turns the broad-specificity PP1C (catalytic subunit) into a myosin regulatory-light chain-specific phosphatase
- R= arginine & K= lysine are positively charged residues that fit the negatively charged acidic groove- Dephosphorylation of myosin regulatory light chain causes smooth muscle cell relaxation (no hydrolysis of ATP)
Role of the phosphatase calcineurin in antigen-mediated T-cell activation (followed by clonal expansion (adaptive immunity))
the activated T-cell receptor induces a Ca2+ signal that binds calcineurin and activates the catalytic subunit (CnA) (PP2B), leading to dephosphorylation
and nuclear translocation of the transcription factor NFAT
NFAT=nuclear factor of activated T-cells
action of protein phosphatase
tyrosine protein phosphates (PTP)
two step mechanism of action of protein tyrosine phosphatases
Tyrosine phosphatase as an inactivator of insulin signalling: tyrosine phosphatase 1B (PTP1B) dephosphorylates the insulin receptor
Certain tyrosine phosphatases have tumour suppressor
functions (by opposing to deragulated tyrosine
protein kinases)
tyrosine phosphatase as an activator of Src: dephosphorylation of the
C-terminal tyrosine phosphate by CD45
the SH2 domain bound to the C-
terminal phosphotyrosine
keeps the kinase in an incompetent conformation
dephosphorylation removes this
constraint and is followed by
autophosphorylation. The kinase is now
fully competent
PTEN qualifies by its structure and its sequence as a tyrosine phosphatase but it prefers inositol lipids
and acts as a inositol lipid phosphatase (important tumour suppressor role)
PTEN removes the phosphates that have been added by PI 3-kinase
PI 3-kinase is activated by growth factors (including insulin) and plays an important role in growth regulation and cell survival
this explains why loss of PTEN is involved in cell transformation(cancer development)