Lectures_6_and_7-phosphorylation

P proteins on tyrosine residues(less than 1 –

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Unformatted text preview: P proteins on tyrosine residues (less than 1%) – “dual-function” kinases can P all 3 – In all cases, the kinases transfer the terminal P from ATP to the hydroxyl moiety of the given amino acid – Requires Mg2+ – P’lation changes the charge of the protein substrate alters conformation alters function Schema of phosphorylation Ser-Thr Kinases • The most well-investigated protein kinases in the brain are those stimulated by cAMP, cGMP, Ca2+ and DAG • cAMP-dependent kinases (PKA) – cAMP (stimulated upon Gs-signaling ) binds to regulatory subunits of PKA and causes their dissociation from the catalytic subunits – PKA is high compartmentalized but associated with PM, cytoplasm and nucleus – Anchored by A kinase Anchor Proteins (AKAPs) , which bind to the regulatory subunits (keep the protein kinase in close proximity to signal transduction molecules that it P’lates) • cGMP-dependent kinases (PKG) – cGMP binds to the regulatory domain of PKG but the kinase does not dissociate more limited range of function – Has a more restricted expression pattern than PKA smaller number of 2 nd messenger actions • Protein Kinase C – Activated by Ca2+, in conjunction with DAG (but depends on the isozyme; “conventional” require both; “novel” are Ca-independent) – Activation tends to move kinase from cytoplasm to the PM – When activated, PKC binds to RACKs (receptors for activated C kinase) , which are aligned in series at the plasma membrane and bring PKC closer to substrates) Protein kinases PKA : cAMP binds to 2 regulatory subunits Inhibited by endogenous protein called PKI (protein kinase inhibitor) PKG: cGMP binds to regulatory subunit PKC : DAG binds to C1, Ca2+ binds to C2; when bound, inhibitory pseudosubstrate is relieved and enzyme activated • Calcium/calmodulin-dependent protein kinases (CaMK’s) – Calmodulin is a cytoplasmic protein capable of binding 2 Ca2+ molecules Ca2+/calmodulin activates CaMKs – At least 6 major types of CaMKs in the brain – CaMKII has a broad cellular distribution and substrate specificity; mediates many of the second messenger effects of Ca2+; contains regulatory domain and a catalytic domain – activated by Ca2+/calmodulin binding to the regulatory domain dissociates regulatory and catalytic domains P on Ser auto-P at Ca2+/calmodulin site (now independent of message) – CaMKI and CaMKIV can be activated not only by Ca2+/calmodulin, but also by P’lation by CaMK kinases (which may also be Ca2+/calmodulin-dependent and inhibited by PKA cross-talk between different 2 nd messenger systems) Mitogen-activated Protein Kinases (MAPKs) • Very important Ser-Thr kinases that are not activated directly by 2 nd messenger systems; rather are activated by Receptor Tyrosine Kinases (RTKs), which in turn activate small G-proteins •...
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P proteins on tyrosine residues(less than 1 –...

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