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- PDB-9dw7: Dephosphorylated CFTR in 1:2 complex with PKA-C -

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Basic information

Entry
Database: PDB / ID: 9dw7
TitleDephosphorylated CFTR in 1:2 complex with PKA-C
Components
  • Cystic fibrosis transmembrane conductance regulator
  • cAMP-dependent protein kinase catalytic subunit alpha
  • cystic fibrosis transmembrane conductance regulator
KeywordsHYDROLASE / CFTR / PKA / complex
Function / homology
Function and homology information


positive regulation of voltage-gated chloride 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 / Rap1 signalling ...positive regulation of voltage-gated chloride 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 / Rap1 signalling / Ion homeostasis / transepithelial water transport / RHO GTPases regulate CFTR trafficking / PKA activation in glucagon signalling / DARPP-32 events / CREB1 phosphorylation through the activation of Adenylate Cyclase / GPER1 signaling / Factors involved in megakaryocyte development and platelet production / 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 / RET signaling / AURKA Activation by TPX2 / amelogenesis / Interleukin-3, Interleukin-5 and GM-CSF signaling / intracellular pH elevation / Recruitment of NuMA to mitotic centrosomes / VEGFA-VEGFR2 Pathway / PKA activation / MAPK6/MAPK4 signaling / GLI3 is processed to GLI3R by the proteasome / chloride channel inhibitor activity / : / 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 / chloride channel regulator activity / vesicle docking involved in exocytosis / membrane hyperpolarization / cAMP-dependent protein kinase / regulation of protein processing / chloride transmembrane transporter activity / 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 / regulation of osteoblast differentiation / cellular response to cold / Mitochondrial protein degradation / sperm capacitation / cholesterol biosynthetic process / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / negative regulation of glycolytic process through fructose-6-phosphate / ciliary base / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / protein kinase A regulatory subunit binding / RHOQ GTPase cycle / chloride channel activity / intracellular potassium ion homeostasis / mesoderm formation / positive regulation of exocytosis / plasma membrane raft / axoneme / ATPase-coupled transmembrane transporter activity / chloride channel complex / positive regulation of insulin secretion involved in cellular response to glucose stimulus / ABC-type transporter activity / sperm flagellum / postsynaptic modulation of chemical synaptic transmission / regulation of proteasomal protein catabolic process / 14-3-3 protein binding / negative regulation of TORC1 signaling / positive regulation of gluconeogenesis / protein serine/threonine/tyrosine kinase activity / cellular response to glucagon stimulus / acrosomal vesicle / cellular response to forskolin / protein export from nucleus / positive regulation of phagocytosis / chloride transmembrane transport / response to endoplasmic reticulum stress / cellular response to cAMP / positive regulation of protein export from nucleus / negative regulation of smoothened signaling pathway / neural tube closure / PDZ domain binding / neuromuscular junction / cellular response to glucose stimulus / establishment of localization in cell / clathrin-coated endocytic vesicle membrane / positive regulation of cholesterol biosynthetic process / Defective CFTR causes cystic fibrosis / Late endosomal microautophagy
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
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / 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: 6 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
K: cAMP-dependent protein kinase catalytic subunit alpha
A: Cystic fibrosis transmembrane conductance regulator
G: cAMP-dependent protein kinase catalytic subunit alpha
B: cystic fibrosis transmembrane conductance regulator
hetero molecules


Theoretical massNumber of molelcules
Total (without water)251,8817
Polymers251,3264
Non-polymers5553
Water00
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

#1: Protein cAMP-dependent protein kinase catalytic subunit alpha / PKA C-alpha


Mass: 40677.652 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Bos taurus (domestic cattle) / References: UniProt: P00517, cAMP-dependent protein kinase
#2: 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: 168335.453 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CFTR, ABCC7 / Production host: Homo sapiens (human)
References: UniProt: P13569, channel-conductance-controlling ATPase
#3: Protein/peptide cystic fibrosis transmembrane conductance regulator


Mass: 1635.006 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human)
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-ANP / PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER


Mass: 506.196 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H17N6O12P3 / Feature type: SUBJECT OF INVESTIGATION / Comment: AMP-PNP, energy-carrying molecule analogue*YM
Has ligand of interestY
Has protein modificationN

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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: dephosphorylated CFTR in 1:2 complex with PKA-C / Type: COMPLEX / Entity ID: #1-#3 / 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
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 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: 6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 29826 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0029028
ELECTRON MICROSCOPYf_angle_d0.41812562
ELECTRON MICROSCOPYf_dihedral_angle_d3.9041821
ELECTRON MICROSCOPYf_chiral_restr0.0391718
ELECTRON MICROSCOPYf_plane_restr0.0021813

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