6bys
Structures of the PKA RI alpha holoenzyme with the FLHCC driver J-PKAc alpha or native PRKAc alpha
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 PubMedFibrolamellar hepatocellular carcinoma (FLHCC) is driven by J-PKAcalpha, a kinase fusion chimera of the J domain of DnaJB1 with PKAcalpha, the catalytic subunit of protein kinase A (PKA). Here we report the crystal structures of the chimeric fusion RIalpha2:J-PKAcalpha2 holoenzyme formed by J-PKAcalpha and the PKA regulatory (R) subunit RIalpha, and the wild-type (WT) RIalpha2:PKAcalpha2 holoenzyme. The chimeric and WT RIalpha holoenzymes have quaternary structures different from the previously solved WT RIbeta and RIIbeta holoenzymes. The WT RIalpha holoenzyme showed the same configuration as the chimeric RIalpha2:J-PKAcalpha2 holoenzyme and a distinct second conformation. The J domains are positioned away from the symmetrical interface between the two RIalpha:J-PKAcalpha heterodimers in the chimeric fusion holoenzyme and are highly dynamic. The structural and dynamic features of these holoenzymes enhance our understanding of the fusion chimera protein J-PKAcalpha that drives FLHCC as well as the isoform specificity of PKA. Structures of the PKA RIalpha Holoenzyme with the FLHCC Driver J-PKAcalpha or Wild-Type PKAcalpha.,Cao B, Lu TW, Martinez Fiesco JA, Tomasini M, Fan L, Simon SM, Taylor SS, Zhang P Structure. 2019 Mar 15. pii: S0969-2126(19)30079-6. doi:, 10.1016/j.str.2019.03.001. PMID:30905674[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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