| Structural highlights
6mm8 is a 2 chain structure with sequence from Lk3 transgenic mice. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , |
| NonStd Res: | , |
| Gene: | Prkaca, Pkaca (LK3 transgenic mice), Ryr2 (LK3 transgenic mice) |
| 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).[1] [2] [3] [RYR2_MOUSE] Calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm and thereby plays a key role in triggering cardiac muscle contraction. Aberrant channel activation can lead to cardiac arrhythmia. In cardiac myocytes, calcium release is triggered by increased Ca(2+) levels due to activation of the L-type calcium channel CACNA1C. The calcium channel activity is modulated by formation of heterotetramers with RYR3. Required for cellular calcium ion homeostasis. Required for embryonic heart development.[4] [5] [6] [7]
References
- ↑ Nolan MA, Babcock DF, Wennemuth G, Brown W, Burton KA, McKnight GS. Sperm-specific protein kinase A catalytic subunit Calpha2 orchestrates cAMP signaling for male fertility. Proc Natl Acad Sci U S A. 2004 Sep 14;101(37):13483-8. Epub 2004 Aug 31. PMID:15340140 doi:10.1073/pnas.0405580101
- ↑ Pirino G, Wescott MP, Donovan PJ. Protein kinase A regulates resumption of meiosis by phosphorylation of Cdc25B in mammalian oocytes. Cell Cycle. 2009 Feb 15;8(4):665-70. Epub 2009 Feb 14. PMID:19223768
- ↑ Baker MA, Hetherington L, Curry B, Aitken RJ. Phosphorylation and consequent stimulation of the tyrosine kinase c-Abl by PKA in mouse spermatozoa; its implications during capacitation. Dev Biol. 2009 Sep 1;333(1):57-66. doi: 10.1016/j.ydbio.2009.06.022. Epub 2009, Jun 26. PMID:19560455 doi:10.1016/j.ydbio.2009.06.022
- ↑ Zhao M, Li P, Li X, Zhang L, Winkfein RJ, Chen SR. Molecular identification of the ryanodine receptor pore-forming segment. J Biol Chem. 1999 Sep 10;274(37):25971-4. PMID:10473538
- ↑ Takeshima H, Komazaki S, Hirose K, Nishi M, Noda T, Iino M. Embryonic lethality and abnormal cardiac myocytes in mice lacking ryanodine receptor type 2. EMBO J. 1998 Jun 15;17(12):3309-16. PMID:9628868 doi:10.1093/emboj/17.12.3309
- ↑ van Oort RJ, McCauley MD, Dixit SS, Pereira L, Yang Y, Respress JL, Wang Q, De Almeida AC, Skapura DG, Anderson ME, Bers DM, Wehrens XH. Ryanodine receptor phosphorylation by calcium/calmodulin-dependent protein kinase II promotes life-threatening ventricular arrhythmias in mice with heart failure. Circulation. 2010 Dec 21;122(25):2669-79. doi: 10.1161/CIRCULATIONAHA.110.982298., Epub 2010 Nov 15. PMID:21098440 doi:10.1161/CIRCULATIONAHA.110.982298
- ↑ Guo T, Cornea RL, Huke S, Camors E, Yang Y, Picht E, Fruen BR, Bers DM. Kinetics of FKBP12.6 binding to ryanodine receptors in permeabilized cardiac myocytes and effects on Ca sparks. Circ Res. 2010 Jun 11;106(11):1743-52. doi: 10.1161/CIRCRESAHA.110.219816. Epub, 2010 Apr 29. PMID:20431056 doi:10.1161/CIRCRESAHA.110.219816
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