4x6q

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==An Isoform-specific Myristylation Switch Targets RIIb PKA Holoenzymes to Membranes==
==An Isoform-specific Myristylation Switch Targets RIIb PKA Holoenzymes to Membranes==
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<StructureSection load='4x6q' size='340' side='right' caption='[[4x6q]], [[Resolution|resolution]] 2.52&Aring;' scene=''>
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<StructureSection load='4x6q' size='340' side='right'caption='[[4x6q]], [[Resolution|resolution]] 2.52&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4x6q]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4X6Q OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4X6Q FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4x6q]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4X6Q OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4X6Q FirstGlance]. <br>
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</td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.52&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4x6r|4x6r]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/cAMP-dependent_protein_kinase cAMP-dependent protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.11 2.7.11.11] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4x6q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x6q OCA], [https://pdbe.org/4x6q PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4x6q RCSB], [https://www.ebi.ac.uk/pdbsum/4x6q PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4x6q ProSAT]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4x6q FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4x6q OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4x6q RCSB], [http://www.ebi.ac.uk/pdbsum/4x6q PDBsum]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/KAP3_MOUSE KAP3_MOUSE]] Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells. Type II regulatory chains mediate membrane association by binding to anchoring proteins, including the MAP2 kinase. [[http://www.uniprot.org/uniprot/KAPCA_MOUSE KAPCA_MOUSE]] Phosphorylates a large number of substrates in the cytoplasm and the nucleus. Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis. Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA, TRPC1 and VASP. RORA is activated by phosphorylation. Required for glucose-mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts. Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa-B-alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VASP. Prevents the antiproliferative and anti-invasive effects of alpha-difluoromethylornithine in breast cancer cells when activated. RYR2 channel activity is potentiated by phosphorylation in presence of luminal Ca(2+), leading to reduced amplitude and increased frequency of store overload-induced Ca(2+) release (SOICR) characterized by an increased rate of Ca(2+) release and propagation velocity of spontaneous Ca(2+) waves, despite reduced wave amplitude and resting cytosolic Ca(2+). TRPC1 activation by phosphorylation promotes Ca(2+) influx, essential for the increase in permeability induced by thrombin in confluent endothelial monolayers. PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Regulates negatively tight junction (TJs) in ovarian cancer cells via CLDN3 phosphorylation. NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding. Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis. Isoform 2 phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation. Prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation. May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT).<ref>PMID:15340140</ref> <ref>PMID:19223768</ref> <ref>PMID:19560455</ref>
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[https://www.uniprot.org/uniprot/KAP3_MOUSE KAP3_MOUSE] Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells. Type II regulatory chains mediate membrane association by binding to anchoring proteins, including the MAP2 kinase.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Cyclic AMP-dependent protein kinase (PKA) is regulated in part by N-terminal myristylation of its catalytic (C) subunit. Structural information about the role of myristylation in membrane targeting of PKA has been limited. In mammalian cells there are four functionally non-redundant PKA regulatory subunits (RIalpha, RIbeta, RIIalpha, and RIIbeta). PKA is assembled as an inactive R2C2 holoenzyme in cells. To explore the role of N-myristylation in membrane targeting of PKA holoenzymes, we solved crystal structures of RIalpha:myrC and RIIbeta2:myrC2, and showed that the N-terminal myristylation site in the myrC serves as a flexible "switch" that can potentially be mobilized for membrane anchoring of RII, but not RI, holoenzymes. Furthermore, we synthesized nanodiscs and showed by electron microscopy that membrane targeting through the myristic acid is specific for the RII holoenzyme. This membrane-anchoring myristylation switch is independent of A Kinase Anchoring Proteins (AKAPs) that target PKA to membranes by other mechanisms.
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An Isoform-Specific Myristylation Switch Targets Type II PKA Holoenzymes to Membranes.,Zhang P, Ye F, Bastidas AC, Kornev AP, Wu J, Ginsberg MH, Taylor SS Structure. 2015 Aug 5. pii: S0969-2126(15)00288-9. doi:, 10.1016/j.str.2015.07.007. PMID:26278174<ref>PMID:26278174</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4x6q" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[CAMP-dependent protein kinase 3D structures|CAMP-dependent protein kinase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: CAMP-dependent protein kinase]]
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[[Category: Large Structures]]
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[[Category: Bastidas, A C]]
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[[Category: Mus musculus]]
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[[Category: Ginsberg, M H]]
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[[Category: Bastidas AC]]
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[[Category: Kornev, A P]]
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[[Category: Ginsberg MH]]
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[[Category: Taylor, S S]]
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[[Category: Kornev AP]]
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[[Category: Ye, F]]
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[[Category: Taylor SS]]
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[[Category: Zhang, P]]
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[[Category: Ye F]]
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[[Category: Membrane binding]]
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[[Category: Zhang P]]
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[[Category: Molecular switch]]
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[[Category: Pka]]
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[[Category: Transferase]]
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An Isoform-specific Myristylation Switch Targets RIIb PKA Holoenzymes to Membranes

PDB ID 4x6q

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