5jr7

Crystal structure of an ACRDYS heterodimer [RIa(92-365):C] of PKA

spinqualitylabelsall models 5jr7, resolution 3.56Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5jr7 is a 4 chain structure with sequence from Bovin and Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ADP NonStd Res: SEP, TPO Gene: Prkaca, Pkaca (LK3 transgenic mice), PRKAR1A (BOVIN) Activity: cAMP-dependent protein kinase, with EC number 2.7.11.11 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [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). [KAP0_BOVIN] Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells. Publication Abstract from PubMed Most disease-related mutations that impair cAMP protein kinase A (PKA) signaling are present within the regulatory (R) PKA RI alpha-subunit (RIalpha). Although mutations in the PRKAR1A gene are linked to Carney complex (CNC) disease and, more recently, to acrodysostosis-1 (ACRDYS1), the two diseases show contrasting phenotypes. While CNC mutations cause increased PKA activity, ACRDYS1 mutations result in decreased PKA activity and cAMP resistant holoenzymes. Mapping the ACRDYS1 disease mutations reveals their localization to the second of two tandem cAMP-binding (CNB) domains (CNB-B), and here, we characterize a recurrent deletion mutant where the last 14 residues are missing. The crystal structure of a monomeric form of this mutant (RIalpha92-365) bound to the catalytic (C)-subunit reveals the dysfunctional regions of the RIalpha subunit. Beyond the missing residues, the entire capping motif is disordered (residues 357-379) and explains the disrupted cAMP binding. Moreover, the effects of the mutation extend far beyond the CNB-B domain and include the active site and N-lobe of the C-subunit, which is in a partially open conformation with the C-tail disordered. A key residue that contributes to this crosstalk, D267, is altered in our structure, and we confirmed its functional importance by mutagenesis. In particular, the D267 interaction with Arg241, a residue shown earlier to be important for allosteric regulation, is disrupted, thereby strengthening the interaction of D267 with the C-subunit residue Arg194 at the R:C interface. We see here how the switch between active (cAMP-bound) and inactive (holoenzyme) conformations is perturbed and how the dynamically controlled crosstalk between the helical domains of the two CNB domains is necessary for the functional regulation of PKA activity. Structure of a PKA RIalpha Recurrent Acrodysostosis Mutant Explains Defective cAMP-Dependent Activation.,Bruystens JG, Wu J, Fortezzo A, Del Rio J, Nielsen C, Blumenthal DK, Rock R, Stefan E, Taylor SS J Mol Biol. 2016 Dec 4;428(24 Pt B):4890-4904. doi: 10.1016/j.jmb.2016.10.033., Epub 2016 Nov 5. PMID:27825928 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also CAMP-dependent protein kinase 3D structures

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