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- PDB-9dw9: Phosphorylated (E1371Q)CFTR in complex with PKA-C -

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Basic information

Entry
Database: PDB / ID: 9dw9
TitlePhosphorylated (E1371Q)CFTR in complex with PKA-C
Components
  • Cystic fibrosis transmembrane conductance regulator
  • cAMP-dependent protein kinase catalytic subunit alpha
KeywordsHYDROLASE / CFTR / PKA / complex
Function / homology
Function and homology information


positive regulation of voltage-gated chloride channel activity / positive regulation of cyclic nucleotide-gated ion channel activity / Sec61 translocon complex binding / channel-conductance-controlling ATPase / intracellularly ATP-gated chloride channel activity / CD209 (DC-SIGN) signaling / HDL assembly / Regulation of insulin secretion / positive regulation of enamel mineralization / transepithelial water transport ...positive regulation of voltage-gated chloride channel activity / positive regulation of cyclic nucleotide-gated ion channel activity / Sec61 translocon complex binding / channel-conductance-controlling ATPase / intracellularly ATP-gated chloride channel activity / CD209 (DC-SIGN) signaling / HDL assembly / Regulation of insulin secretion / positive regulation of enamel mineralization / transepithelial water transport / Rap1 signalling / RHO GTPases regulate CFTR trafficking / Ion homeostasis / PKA activation in glucagon signalling / DARPP-32 events / CREB1 phosphorylation through the activation of Adenylate Cyclase / GPER1 signaling / Loss of Nlp from mitotic centrosomes / Recruitment of mitotic centrosome proteins and complexes / Loss of proteins required for interphase microtubule organization from the centrosome / Anchoring of the basal body to the plasma membrane / AURKA Activation by TPX2 / Factors involved in megakaryocyte development and platelet production / RET signaling / intracellular pH elevation / amelogenesis / Interleukin-3, Interleukin-5 and GM-CSF signaling / Recruitment of NuMA to mitotic centrosomes / chloride channel inhibitor activity / VEGFA-VEGFR2 Pathway / PKA activation / ATPase-coupled inorganic anion transmembrane transporter activity / MAPK6/MAPK4 signaling / GLI3 is processed to GLI3R by the proteasome / Regulation of PLK1 Activity at G2/M Transition / Hedgehog 'off' state / Golgi-associated vesicle membrane / multicellular organismal-level water homeostasis / cholesterol transport / bicarbonate transport / bicarbonate transmembrane transporter activity / membrane hyperpolarization / vesicle docking involved in exocytosis / chloride channel regulator activity / chloride transmembrane transporter activity / cAMP-dependent protein kinase / regulation of protein processing / cAMP-dependent protein kinase activity / protein localization to lipid droplet / cAMP-dependent protein kinase complex / regulation of bicellular tight junction assembly / cellular response to parathyroid hormone stimulus / cellular response to cold / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / regulation of osteoblast differentiation / sperm capacitation / Mitochondrial protein degradation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / cholesterol biosynthetic process / ciliary base / negative regulation of glycolytic process through fructose-6-phosphate / protein kinase A regulatory subunit binding / chloride channel activity / RHOQ GTPase cycle / positive regulation of exocytosis / positive regulation of insulin secretion involved in cellular response to glucose stimulus / mesoderm formation / sperm flagellum / plasma membrane raft / axoneme / ATPase-coupled transmembrane transporter activity / chloride channel complex / ABC-type transporter activity / postsynaptic modulation of chemical synaptic transmission / negative regulation of TORC1 signaling / cellular response to cAMP / 14-3-3 protein binding / regulation of proteasomal protein catabolic process / positive regulation of gluconeogenesis / cellular response to forskolin / protein serine/threonine/tyrosine kinase activity / cellular response to glucagon stimulus / chloride transmembrane transport / response to endoplasmic reticulum stress / protein export from nucleus / acrosomal vesicle / positive regulation of protein export from nucleus / PDZ domain binding / negative regulation of smoothened signaling pathway / isomerase activity / establishment of localization in cell / neural tube closure / positive regulation of cholesterol biosynthetic process / Defective CFTR causes cystic fibrosis / clathrin-coated endocytic vesicle membrane / cellular response to glucose stimulus / Late endosomal microautophagy / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / neuromuscular junction
Similarity search - Function
: / CFTR regulator domain / Cystic fibrosis TM conductance regulator (CFTR), regulator domain / Cystic fibrosis transmembrane conductance regulator / : / cAMP-dependent protein kinase catalytic subunit / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / ABC transporter transmembrane region ...: / CFTR regulator domain / Cystic fibrosis TM conductance regulator (CFTR), regulator domain / Cystic fibrosis transmembrane conductance regulator / : / cAMP-dependent protein kinase catalytic subunit / Extension to Ser/Thr-type protein kinases / AGC-kinase, C-terminal / AGC-kinase C-terminal domain profile. / ABC transporter transmembrane region / ABC transporter type 1, transmembrane domain / ABC transporter integral membrane type-1 fused domain profile. / ABC transporter type 1, transmembrane domain superfamily / ABC transporter-like, conserved site / ABC transporters family signature. / ABC transporter / ABC transporter-like, ATP-binding domain / ATP-binding cassette, ABC transporter-type domain profile. / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / ATPases associated with a variety of cellular activities / AAA+ ATPase domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ADENOSINE-5'-TRIPHOSPHATE / CHOLESTEROL / DECANE / UNDECANE / cAMP-dependent protein kinase catalytic subunit alpha / Cystic fibrosis transmembrane conductance regulator
Similarity search - Component
Biological speciesHomo sapiens (human)
Bos taurus (domestic cattle)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsFiedorczuk, K. / Chen, J. / Csanady, L.
Funding support United States, 2items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
Cystic Fibrosis Foundation United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2024
Title: The structures of protein kinase A in complex with CFTR: Mechanisms of phosphorylation and noncatalytic activation.
Authors: Karol Fiedorczuk / Iordan Iordanov / Csaba Mihályi / Andras Szollosi / László Csanády / Jue Chen /
Abstract: Protein kinase A (PKA) is a key regulator of cellular functions by selectively phosphorylating numerous substrates, including ion channels, enzymes, and transcription factors. It has long served as a ...Protein kinase A (PKA) is a key regulator of cellular functions by selectively phosphorylating numerous substrates, including ion channels, enzymes, and transcription factors. It has long served as a model system for understanding the eukaryotic kinases. Using cryoelectron microscopy, we present complex structures of the PKA catalytic subunit (PKA-C) bound to a full-length protein substrate, the cystic fibrosis transmembrane conductance regulator (CFTR)-an ion channel vital to human health. CFTR gating requires phosphorylation of its regulatory (R) domain. Unphosphorylated CFTR engages PKA-C at two locations, establishing two "catalytic stations" near to, but not directly involving, the R domain. This configuration, coupled with the conformational flexibility of the R domain, permits transient interactions of the eleven spatially separated phosphorylation sites. Furthermore, we determined two structures of the open-pore CFTR stabilized by PKA-C, providing a molecular basis to understand how PKA-C stimulates CFTR currents even in the absence of phosphorylation.
History
DepositionOct 8, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 13, 2024Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cystic fibrosis transmembrane conductance regulator
G: cAMP-dependent protein kinase catalytic subunit alpha
hetero molecules


Theoretical massNumber of molelcules
Total (without water)212,35721
Polymers209,1722
Non-polymers3,18519
Water543
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 2 types, 2 molecules AG

#1: Protein Cystic fibrosis transmembrane conductance regulator / CFTR / ATP-binding cassette sub-family C member 7 / Channel conductance-controlling ATPase / cAMP- ...CFTR / ATP-binding cassette sub-family C member 7 / Channel conductance-controlling ATPase / cAMP-dependent chloride channel


Mass: 168414.453 Da / Num. of mol.: 1 / Mutation: E1371Q
Source method: isolated from a genetically manipulated source
Details: phosphorylated (E1371Q)CFTR / Source: (gene. exp.) Homo sapiens (human) / Gene: CFTR, ABCC7 / Production host: Homo sapiens (human)
References: UniProt: P13569, channel-conductance-controlling ATPase
#2: Protein cAMP-dependent protein kinase catalytic subunit alpha / PKA C-alpha


Mass: 40757.633 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: PKA-C / Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: PRKACA / Production host: Bos taurus (domestic cattle) / References: UniProt: P00517, cAMP-dependent protein kinase

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Non-polymers , 7 types, 22 molecules

#3: Chemical ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H46O
#4: Chemical
ChemComp-D10 / DECANE


Mass: 142.282 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H22
#5: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#6: Chemical ChemComp-ATP / ADENOSINE-5'-TRIPHOSPHATE


Mass: 507.181 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C10H16N5O13P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: ATP, energy-carrying molecule*YM
#7: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#8: Chemical ChemComp-UND / UNDECANE / LIPID FRAGMENT


Mass: 156.308 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C11H24
#9: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Phosphorylated (E1371Q)CFTR in complex with PKA-C / Type: COMPLEX / Entity ID: #1-#2 / Source: MULTIPLE SOURCES
Molecular weightValue: 0.21 MDa / Experimental value: NO
Source (natural)Organism: Bos taurus (domestic cattle)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
SpecimenConc.: 5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid type: Quantifoil R0.6/1
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 52.5 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 47950 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00312498
ELECTRON MICROSCOPYf_angle_d0.55916908
ELECTRON MICROSCOPYf_dihedral_angle_d8.3611770
ELECTRON MICROSCOPYf_chiral_restr0.0411915
ELECTRON MICROSCOPYf_plane_restr0.0032077

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