9edc
Reset Type-I Protein Kinase A Holoenzyme
Structural highlights
FunctionKAPCA_HUMAN 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). Phosphorylates APOBEC3G and AICDA.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] Publication Abstract from PubMedHow protein kinase A (PKA) is reset to a basal state following 3'5'-cyclic adenosine monophosphate (cAMP)-mediated activation is unknown. Here we describe the mechanism of cAMP-PKA type I signal termination leading to a reset of PKA by holoenzyme formation through the obligatory action of phosphodiesterases (PDEs). We report a catalytic subunit (Calpha)-assisted mechanism for the reset of type I PKA and describe for the first time multiple structures of the reset PKA holoenzyme (RIalpha(2):Calpha(2)) that capture an ensemble of multiple conformational end-states through integrative electron microscopy and structural mass spectrometry approaches. Together these complementary methods highlight the large conformational dynamics of the regulatory subunit (RIalpha) within the tetrameric reset PKA holoenzyme. The cAMP-free reset PKA holoenzyme adopts multiple distinct conformations of RIalpha with contributions from the N-terminal linker and CNB-B dynamics. Our findings highlight the interplay between RIalpha, Calpha, and PDEs (PDE8) in cAMP-PKA signalosomes to offer a new paradigm for PDE-mediated regulation of cAMP-PKA signaling. Multiplicity of Regulatory Subunit Conformations Defines Structural Ensemble of Reset Protein Kinase A Holoenzyme.,Venkatakrishnan V, Laremore TN, Buckley TSC, Armache JP, Anand GS J Am Chem Soc. 2025 Apr 16. doi: 10.1021/jacs.4c16269. PMID:40241376[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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