OCA at 07:23, 29 October 2025

2025-10-29T07:23:00Z

← Older revision		Revision as of 07:23, 29 October 2025
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	~~'''Unreleased structure'''~~

	~~The entry~~ 9o7v is ~~ON HOLD until Paper~~ Publication		==Crystal Structure of the RIb:C Heterodimer of PKA==
			<StructureSection load='9o7v' size='340' side='right'caption='[[9o7v]], [[Resolution\|resolution]] 3.70Å' scene=''>
			== Structural highlights ==
			<table><tr><td colspan='2'>[[9o7v]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9O7V OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9O7V FirstGlance]. <br>
			</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 3.7Å</td></tr>
			<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>
			<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9o7v FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9o7v OCA], [https://pdbe.org/9o7v PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9o7v RCSB], [https://www.ebi.ac.uk/pdbsum/9o7v PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9o7v ProSAT]</span></td></tr>
			</table>
			== Function ==
			[https://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>
			<div style="background-color:#fffaf0;">
			== Publication Abstract from PubMed ==
			The RIbeta subunit of cAMP-dependent protein kinase (PKA) is highly expressed in the brain, yet it remains the least studied of the PKA regulatory subunits (R). As pathologic variants of its gene are increasingly implicated in neurodevelopmental disorders, neurodegeneration, and cancer, gaining more information about the structure/function of RIbeta, and how it differs from RIalpha, has become increasingly important. We previously reported the structure of the RIbeta(2)C(2) holoenzyme, which revealed a novel conformation where ATP binding was stabilized by a head-to-head anti-parallel packing of the C-tail wrapped around the N-lobe of the catalytic subunit (C). Although visible, the Dimerization/Docking Domain was poorly folded and reduced. Since RIbeta is oxidized in brain tissues, we asked if oxidation or binding of an A Kinase Anchoring Protein (AKAP) would affect the holoenzyme structure. Oxidation or addition of an AKAP peptide to crystals led to the release of nucleotide. To capture this at higher resolution we crystallized RIbeta(2)C(2) in the presence of an AKAP peptide. This new structure represents an RIbeta:C heterodimer. Density for the D/D domain was missing; ATP was absent, the kinase adopted an open conformation, and the C-terminus of the RIbeta subunit was no longer resolved. Because the crosstalk between ATP and cAMP in the R:C complex appears to be mediated by the two N3A motifs (N3A(A) and N3A(B)) as well as by the linker, which in free RIbeta is intrinsically disordered, we describe the conserved features of these two motifs as well as the linker and show how each contributes in a unique but coordinated way to allosteric activation of RIbeta holoenzymes by cAMP. A key difference in our RIbeta:C structure is the rotation of the side chain of W260 at the N-terminus of the alphaA Helix in N3A(B). W260, at the R:C interface in the holoenzyme, is also the capping residue for cAMP bound to CNB-A, so we may have actually captured the first step in cAMP activation.

	~~Authors:~~ Wu, J., Ilouz, R.~~, Taylor, S~~.S.		N3A motifs in RIbeta mediate allosteric crosstalk between cAMP and ATP in PKA activation.,Wu J, Bruystens JGH, Sahoo P, Bubis J, Maillard RA, Taylor SS, Ilouz R Protein Sci. 2025 Nov;34(11):e70332. doi: 10.1002/pro.70332. PMID:41108566<ref>PMID:41108566</ref>

	~~Description: Crystal Structure~~ of the ~~RIb~~:~~C Heterodimer of PKA~~		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	[[Category: ~~Unreleased Structures~~]]		</div>
	[[Category: ~~Taylor, S.S~~]]		<div class="pdbe-citations 9o7v" style="background-color:#fffaf0;"></div>
	[[Category: ~~Wu, J~~]]		== References ==
	[[Category: Ilouz, R]]		<references/>
			__TOC__
			</StructureSection>
			[[Category: Homo sapiens]]
			[[Category: Large Structures]]
			[[Category: Mus musculus]]
			[[Category: Ilouz R]]
			[[Category: Taylor SS]]
			[[Category: Wu J]]

OCA: Protected "9o7v" [edit=sysop:move=sysop]

2025-04-23T04:05:54Z

Protected "9o7v" [edit=sysop:move=sysop]

← Older revision	Revision as of 04:05, 23 April 2025
(No difference)

OCA: New page: '''Unreleased structure''' The entry 9o7v is ON HOLD until Paper Publication Authors: Wu, J., Ilouz, R., Taylor, S.S. Description: Crystal Structure of the RIb:C Heterodimer of PKA [[C...

2025-04-23T04:05:53Z

New page: '''Unreleased structure''' The entry 9o7v is ON HOLD until Paper Publication Authors: Wu, J., Ilouz, R., Taylor, S.S. Description: Crystal Structure of the RIb:C Heterodimer of PKA [[C...

New page

'''Unreleased structure'''

The entry 9o7v is ON HOLD until Paper Publication

Authors: Wu, J., Ilouz, R., Taylor, S.S.

Description: Crystal Structure of the RIb:C Heterodimer of PKA
[[Category: Unreleased Structures]]
[[Category: Taylor, S.S]]
[[Category: Wu, J]]
[[Category: Ilouz, R]]

9o7v - Revision history

OCA at 07:23, 29 October 2025

OCA: Protected "9o7v" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 9o7v is ON HOLD until Paper Publication Authors: Wu, J., Ilouz, R., Taylor, S.S. Description: Crystal Structure of the RIb:C Heterodimer of PKA [[C...