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- EMDB-47238: Dephosphorylated (E1371Q)CFTR in complex with PKA-C -

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Entry
Database: EMDB / ID: EMD-47238
TitleDephosphorylated (E1371Q)CFTR in complex with PKA-C
Map dataDephosphorylated (E1371Q)CFTR in complex with PKA-C
Sample
  • Complex: Dephosphorylated (E1371Q)CFTR in complex with PKA-C
    • Protein or peptide: Cystic fibrosis transmembrane conductance regulator
    • Protein or peptide: cAMP-dependent protein kinase catalytic subunit alpha
  • Ligand: N-(2-phenylethyl)adenosine 5'-(tetrahydrogen triphosphate)
  • Ligand: MAGNESIUM ION
  • Ligand: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER
KeywordsCFTR / PKA / complex / HYDROLASE
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
cAMP-dependent protein kinase catalytic subunit alpha / Cystic fibrosis transmembrane conductance regulator
Similarity search - Component
Biological speciesBos taurus (domestic cattle) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 Å
AuthorsFiedorczuk K / Chen J / Csanady L
Funding support United States, 2 items
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, 2024-
Header (metadata) releaseNov 13, 2024-
Map releaseNov 13, 2024-
UpdateMay 28, 2025-
Current statusMay 28, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47238.png

Downloads & links

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Map

FileDownload / File: emd_47238.map.gz / Format: CCP4 / Size: 325 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationDephosphorylated (E1371Q)CFTR in complex with PKA-C
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.68 Å/pix.
x 440 pix.
= 297.44 Å		0.68 Å/pix.
x 440 pix.
= 297.44 Å		0.68 Å/pix.
x 440 pix.
= 297.44 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.676 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.27
Minimum - Maximum-0.7247152 - 1.2772466
Average (Standard dev.)0.0023854512 (±0.034518808)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions440440440
Spacing440440440
CellA=B=C: 297.44 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: half-map 2

Fileemd_47238_half_map_1.map
Annotationhalf-map 2
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half-map 1

Fileemd_47238_half_map_2.map
Annotationhalf-map 1
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Dephosphorylated (E1371Q)CFTR in complex with PKA-C

EntireName: Dephosphorylated (E1371Q)CFTR in complex with PKA-C
Components
  • Complex: Dephosphorylated (E1371Q)CFTR in complex with PKA-C
    • Protein or peptide: Cystic fibrosis transmembrane conductance regulator
    • Protein or peptide: cAMP-dependent protein kinase catalytic subunit alpha
  • Ligand: N-(2-phenylethyl)adenosine 5'-(tetrahydrogen triphosphate)
  • Ligand: MAGNESIUM ION
  • Ligand: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER

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Supramolecule #1: Dephosphorylated (E1371Q)CFTR in complex with PKA-C

SupramoleculeName: Dephosphorylated (E1371Q)CFTR in complex with PKA-C / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Bos taurus (domestic cattle)
Molecular weightTheoretical: 210 KDa

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Macromolecule #1: Cystic fibrosis transmembrane conductance regulator

MacromoleculeName: Cystic fibrosis transmembrane conductance regulator / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: channel-conductance-controlling ATPase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 168.334469 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MQRSPLEKAS VVSKLFFSWT RPILRKGYRQ RLELSDIYQI PSVDSADNLS EKLEREWDRE LASKKNPKLI NALRRCFFWR FMFYGIFLY LGEVTKAVQP LLLGRIIASY DPDNKEERSI AIYLGIGLCL LFIVRTLLLH PAIFGLHHIG MQMRIAMFSL I YKKTLKLS ...String:
MQRSPLEKAS VVSKLFFSWT RPILRKGYRQ RLELSDIYQI PSVDSADNLS EKLEREWDRE LASKKNPKLI NALRRCFFWR FMFYGIFLY LGEVTKAVQP LLLGRIIASY DPDNKEERSI AIYLGIGLCL LFIVRTLLLH PAIFGLHHIG MQMRIAMFSL I YKKTLKLS SRVLDKISIG QLVSLLSNNL NKFDEGLALA HFVWIAPLQV ALLMGLIWEL LQASAFCGLG FLIVLALFQA GL GRMMMKY RDQRAGKISE RLVITSEMIE NIQSVKAYCW EEAMEKMIEN LRQTELKLTR KAAYVRYFNS SAFFFSGFFV VFL SVLPYA LIKGIILRKI FTTISFCIVL RMAVTRQFPW AVQTWYDSLG AINKIQDFLQ KQEYKTLEYN LTTTEVVMEN VTAF WEEGF GELFEKAKQN NNNRKTSNGD DSLFFSNFSL LGTPVLKDIN FKIERGQLLA VAGSTGAGKT SLLMVIMGEL EPSEG KIKH SGRISFCSQF SWIMPGTIKE NIIFGVSYDE YRYRSVIKAC QLEEDISKFA EKDNIVLGEG GITLSGGQRA RISLAR AVY KDADLYLLDS PFGYLDVLTE KEIFESCVCK LMANKTRILV TSKMEHLKKA DKILILHEGS SYFYGTFSEL QNLQPDF SS KLMGCDSFDQ FSAERRNSIL TETLHRFSLE GDAPVSWTET KKQSFKQTGE FGEKRKNSIL NPINSIRKFS IVQKTPLQ M NGIEEDSDEP LERRLSLVPD SEQGEAILPR ISVISTGPTL QARRRQSVLN LMTHSVNQGQ NIHRKTTAST RKVSLAPQA NLTELDIYSR RLSQETGLEI SEEINEEDLK ECFFDDMESI PAVTTWNTYL RYITVHKSLI FVLIWCLVIF LAEVAASLVV LWLLGNTPL QDKGNSTHSR NNSYAVIITS TSSYYVFYIY VGVADTLLAM GFFRGLPLVH TLITVSKILH HKMLHSVLQA P MSTLNTLK AGGILNRFSK DIAILDDLLP LTIFDFIQLL LIVIGAIAVV AVLQPYIFVA TVPVIVAFIM LRAYFLQTSQ QL KQLESEG RSPIFTHLVT SLKGLWTLRA FGRQPYFETL FHKALNLHTA NWFLYLSTLR WFQMRIEMIF VIFFIAVTFI SIL TTGEGE GRVGIILTLA MNIMSTLQWA VNSSIDVDSL MRSVSRVFKF IDMPTEGKPT KSTKPYKNGQ LSKVMIIENS HVKK DDIWP SGGQMTVKDL TAKYTEGGNA ILENISFSIS PGQRVGLLGR TGSGKSTLLS AFLRLLNTEG EIQIDGVSWD SITLQ QWRK AFGVIPQKVF IFSGTFRKNL DPYEQWSDQE IWKVADEVGL RSVIEQFPGK LDFVLVDGGC VLSHGHKQLM CLARSV LSK AKILLLDQPS AHLDPVTYQI IRRTLKQAFA DCTVILCEHR IEAMLECQQF LVIEENKVRQ YDSIQKLLNE RSLFRQA IS PSDRVKLFPH RNSSKCKSKP QIAALKEETE EEVQDTRL

UniProtKB: Cystic fibrosis transmembrane conductance regulator

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Macromolecule #2: cAMP-dependent protein kinase catalytic subunit alpha

MacromoleculeName: cAMP-dependent protein kinase catalytic subunit alpha / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: cAMP-dependent protein kinase
Source (natural)Organism: Bos taurus (domestic cattle)
Molecular weightTheoretical: 40.757633 KDa
SequenceString: MGNAAAAKKG SEQESVKEFL AKAKEDFLKK WENPAQNTAH LDQFERIKTL GTGSFGRVML VKHMETGNHY AMKILDKQKV VKLKQIEHT LNEKRILQAV NFPFLVKLEF SFKDNSNLYM VMEYVPGGEM FSHLRRIGRF SEPHARFYAA QIVLTFEYLH S LDLIYRDL ...String:
MGNAAAAKKG SEQESVKEFL AKAKEDFLKK WENPAQNTAH LDQFERIKTL GTGSFGRVML VKHMETGNHY AMKILDKQKV VKLKQIEHT LNEKRILQAV NFPFLVKLEF SFKDNSNLYM VMEYVPGGEM FSHLRRIGRF SEPHARFYAA QIVLTFEYLH S LDLIYRDL KPENLLIDQQ GYIQVTDFGF AKRVKGRTW(TPO) LCGTPEYLAP EIILSKGYNK AVDWWALGVL IYEMAAGY P PFFADQPIQI YEKIVSGKVR FPSHFSSDLK DLLRNLLQVD LTKRFGNLKN GVNDIKNHKW FATTDWIAIY QRKVEAPFI PKFKGPGDTS NFDDYEEEEI RVSINEKCGK EFSEF

UniProtKB: cAMP-dependent protein kinase catalytic subunit alpha

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Macromolecule #3: N-(2-phenylethyl)adenosine 5'-(tetrahydrogen triphosphate)

MacromoleculeName: N-(2-phenylethyl)adenosine 5'-(tetrahydrogen triphosphate)
type: ligand / ID: 3 / Number of copies: 2 / Formula: B44
Molecular weightTheoretical: 611.33 Da
Chemical component information

ChemComp-B44:
N-(2-phenylethyl)adenosine 5'-(tetrahydrogen triphosphate)

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Macromolecule #4: MAGNESIUM ION

MacromoleculeName: MAGNESIUM ION / type: ligand / ID: 4 / Number of copies: 4 / Formula: MG
Molecular weightTheoretical: 24.305 Da

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Macromolecule #5: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER

MacromoleculeName: PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / type: ligand / ID: 5 / Number of copies: 1 / Formula: ANP
Molecular weightTheoretical: 506.196 Da
Chemical component information

ChemComp-ANP:
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogue*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration5 mg/mL
BufferpH: 7.4
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 68.6 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: EMDB MAP
EMDB ID:

25447

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 38413
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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