- PDB-6wjg: PKA RIIbeta holoenzyme with DnaJB1-PKAc fusion in fibrolamellar h... -
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基本情報
登録情報
データベース: PDB / ID: 6wjg
タイトル
PKA RIIbeta holoenzyme with DnaJB1-PKAc fusion in fibrolamellar hepatoceullar carcinoma
要素
DnaJ homolog subfamily B member 1, cAMP-dependent protein kinase catalytic subunit alpha fusion
cAMP-dependent protein kinase type II-beta regulatory subunit
キーワード
SIGNALING PROTEIN / fibrolamellar hepatoceullar carcinoma / PKA / Kinase
機能・相同性
機能・相同性情報
GPER1 signaling / PKA activation in glucagon signalling / CREB1 phosphorylation through the activation of Adenylate Cyclase / DARPP-32 events / Loss of Nlp from mitotic centrosomes / Recruitment of mitotic centrosome proteins and complexes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / AURKA Activation by TPX2 ...GPER1 signaling / PKA activation in glucagon signalling / CREB1 phosphorylation through the activation of Adenylate Cyclase / DARPP-32 events / Loss of Nlp from mitotic centrosomes / Recruitment of mitotic centrosome proteins and complexes / Loss of proteins required for interphase microtubule organization from the centrosome / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / AURKA Activation by TPX2 / Factors involved in megakaryocyte development and platelet production / Regulation of PLK1 Activity at G2/M Transition / Hedgehog 'off' state / PKA activation / response to antipsychotic drug / PKA-mediated phosphorylation of CREB / PKA-mediated phosphorylation of key metabolic factors / sperm head / ROBO receptors bind AKAP5 / negative regulation of inclusion body assembly / HDL assembly / mitochondrial protein catabolic process / Regulation of glycolysis by fructose 2,6-bisphosphate metabolism / cAMP-dependent protein kinase regulator activity / regulation of protein binding / nucleotide-activated protein kinase complex / high-density lipoprotein particle assembly / Rap1 signalling / Vasopressin regulates renal water homeostasis via Aquaporins / renal water homeostasis / regulation of protein processing / positive regulation of ATP-dependent activity / transcription regulator inhibitor activity / protein localization to lipid droplet / regulation of bicellular tight junction assembly / cellular response to parathyroid hormone stimulus / cell communication by electrical coupling involved in cardiac conduction / cAMP-dependent protein kinase inhibitor activity / cAMP-dependent protein kinase / cellular response to cold / Loss of phosphorylation of MECP2 at T308 / regulation of osteoblast differentiation / CREB1 phosphorylation through the activation of Adenylate Cyclase / sperm capacitation / PKA activation / cAMP-dependent protein kinase activity / ciliary base / negative regulation of glycolytic process through fructose-6-phosphate / cAMP-dependent protein kinase complex / AMP-activated protein kinase activity / postsynaptic modulation of chemical synaptic transmission / cellular response to glucagon stimulus / Triglyceride catabolism / protein kinase A regulatory subunit binding / plasma membrane raft / protein kinase A catalytic subunit binding / PKA activation in glucagon signalling / ATPase activator activity / : / Regulation of MECP2 expression and activity / chaperone cofactor-dependent protein refolding / HSF1-dependent transactivation / mesoderm formation / RET signaling / DARPP-32 events / response to unfolded protein / Interleukin-3, Interleukin-5 and GM-CSF signaling / regulation of cardiac muscle contraction / regulation of cardiac conduction / Regulation of HSF1-mediated heat shock response / sperm flagellum / Attenuation phase / regulation of macroautophagy / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / Hedgehog 'off' state / negative regulation of smoothened signaling pathway / regulation of proteasomal protein catabolic process / regulation of cellular response to heat / cAMP binding / protein folding chaperone / Ion homeostasis / regulation of ryanodine-sensitive calcium-release channel activity / Loss of Nlp from mitotic centrosomes / Loss of proteins required for interphase microtubule organization from the centrosome / forebrain development / positive regulation of gluconeogenesis / Recruitment of mitotic centrosome proteins and complexes / sperm midpiece / negative regulation of TORC1 signaling / Recruitment of NuMA to mitotic centrosomes / protein kinase A signaling / Mitochondrial protein degradation / calcium channel complex / Anchoring of the basal body to the plasma membrane / cellular response to epinephrine stimulus / regulation of cytosolic calcium ion concentration / Hsp70 protein binding / HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand / protein serine/threonine/tyrosine kinase activity / protein export from nucleus 類似検索 - 分子機能
cAMP-dependent protein kinase regulatory subunit / cAMP-dependent protein kinase regulatory subunit, dimerization-anchoring domain / Regulatory subunit of type II PKA R-subunit / RIIalpha, Regulatory subunit portion of type II PKA R-subunit / HSP40/DnaJ peptide-binding / Chaperone DnaJ, C-terminal / DnaJ C terminal domain / Nt-dnaJ domain signature. / DnaJ domain, conserved site / DnaJ domain ...cAMP-dependent protein kinase regulatory subunit / cAMP-dependent protein kinase regulatory subunit, dimerization-anchoring domain / Regulatory subunit of type II PKA R-subunit / RIIalpha, Regulatory subunit portion of type II PKA R-subunit / HSP40/DnaJ peptide-binding / Chaperone DnaJ, C-terminal / DnaJ C terminal domain / Nt-dnaJ domain signature. / DnaJ domain, conserved site / DnaJ domain / DnaJ molecular chaperone homology domain / dnaJ domain profile. / Chaperone J-domain superfamily / DnaJ domain / Cyclic nucleotide-binding domain signature 2. / Cyclic nucleotide-binding domain signature 1. / cAMP-dependent protein kinase catalytic subunit / Cyclic nucleotide-binding, conserved site / Cyclic nucleotide-monophosphate binding domain / Cyclic nucleotide-binding domain / cAMP/cGMP binding motif profile. / Cyclic nucleotide-binding domain / Cyclic nucleotide-binding domain superfamily / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / RmlC-like jelly roll fold / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily 類似検索 - ドメイン・相同性
cAMP-dependent protein kinase type II-beta regulatory subunit / cAMP-dependent protein kinase catalytic subunit alpha / DnaJ homolog subfamily B member 1 類似検索 - 構成要素
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM130389
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
GM34921
米国
National Institutes of Health/Office of the Director
S10OD020011
米国
引用
ジャーナル: PLoS Biol / 年: 2020 タイトル: Structural analyses of the PKA RIIβ holoenzyme containing the oncogenic DnaJB1-PKAc fusion protein reveal protomer asymmetry and fusion-induced allosteric perturbations in ...タイトル: Structural analyses of the PKA RIIβ holoenzyme containing the oncogenic DnaJB1-PKAc fusion protein reveal protomer asymmetry and fusion-induced allosteric perturbations in fibrolamellar hepatocellular carcinoma. 著者: Tsan-Wen Lu / Phillip C Aoto / Jui-Hung Weng / Cole Nielsen / Jennifer N Cash / James Hall / Ping Zhang / Sanford M Simon / Michael A Cianfrocco / Susan S Taylor / 要旨: When the J-domain of the heat shock protein DnaJB1 is fused to the catalytic (C) subunit of cAMP-dependent protein kinase (PKA), replacing exon 1, this fusion protein, J-C subunit (J-C), becomes the ...When the J-domain of the heat shock protein DnaJB1 is fused to the catalytic (C) subunit of cAMP-dependent protein kinase (PKA), replacing exon 1, this fusion protein, J-C subunit (J-C), becomes the driver of fibrolamellar hepatocellular carcinoma (FL-HCC). Here, we use cryo-electron microscopy (cryo-EM) to characterize J-C bound to RIIβ, the major PKA regulatory (R) subunit in liver, thus reporting the first cryo-EM structure of any PKA holoenzyme. We report several differences in both structure and dynamics that could not be captured by the conventional crystallography approaches used to obtain prior structures. Most striking is the asymmetry caused by the absence of the second cyclic nucleotide binding (CNB) domain and the J-domain in one of the RIIβ:J-C protomers. Using molecular dynamics (MD) simulations, we discovered that this asymmetry is already present in the wild-type (WT) RIIβ2C2 but had been masked in the previous crystal structure. This asymmetry may link to the intrinsic allosteric regulation of all PKA holoenzymes and could also explain why most disease mutations in PKA regulatory subunits are dominant negative. The cryo-EM structure, combined with small-angle X-ray scattering (SAXS), also allowed us to predict the general position of the Dimerization/Docking (D/D) domain, which is essential for localization and interacting with membrane-anchored A-Kinase-Anchoring Proteins (AKAPs). This position provides a multivalent mechanism for interaction of the RIIβ holoenzyme with membranes and would be perturbed in the oncogenic fusion protein. The J-domain also alters several biochemical properties of the RIIβ holoenzyme: It is easier to activate with cAMP, and the cooperativity is reduced. These results provide new insights into how the finely tuned allosteric PKA signaling network is disrupted by the oncogenic J-C subunit, ultimately leading to the development of FL-HCC.
A: DnaJ homolog subfamily B member 1, cAMP-dependent protein kinase catalytic subunit alpha fusion B: DnaJ homolog subfamily B member 1, cAMP-dependent protein kinase catalytic subunit alpha fusion C: cAMP-dependent protein kinase type II-beta regulatory subunit D: cAMP-dependent protein kinase type II-beta regulatory subunit
根拠: SAXS, The structure fits the experimental SAXS data well with chi^2=1.2900.
タイプ
名称
対称操作
数
identity operation
1_555
1
Buried area
8400 Å2
ΔGint
-29 kcal/mol
Surface area
54180 Å2
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要素
#1: タンパク質
DnaJhomologsubfamilyBmember1, cAMP-dependentproteinkinasecatalyticsubunitalphafusion / DnaJ protein homolog 1 / Heat shock 40 kDa protein 1 / Heat shock protein 40 / Human DnaJ protein 1 ...DnaJ protein homolog 1 / Heat shock 40 kDa protein 1 / Heat shock protein 40 / Human DnaJ protein 1 / hDj-1 / PKA C-alpha