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- EMDB-47235: Dephosphorylated CFTR in 1:1 complex with PKA-C (site II) -

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Basic information

Entry
Database: EMDB / ID: EMD-47235
TitleDephosphorylated CFTR in 1:1 complex with PKA-C (site II)
Map dataDephosphorylated CFTR in complex with PKA-C (site II)
Sample
  • Complex: dephosphorylated CFTR in 1:1 complex with PKA-C (position II)
    • Protein or peptide: cAMP-dependent protein kinase catalytic subunit alpha
    • Protein or peptide: Cystic fibrosis transmembrane conductance regulator
    • Protein or peptide: Cystic fibrosis transmembrane conductance regulator
KeywordsCFTR / PKA / complex / HYDROLASE
Function / homology
Function and homology information


Sec61 translocon complex binding / CD209 (DC-SIGN) signaling / HDL assembly / Regulation of insulin secretion / channel-conductance-controlling ATPase / intracellularly ATP-gated chloride channel activity / positive regulation of enamel mineralization / Rap1 signalling / Ion homeostasis / RHO GTPases regulate CFTR trafficking ...Sec61 translocon complex binding / CD209 (DC-SIGN) signaling / HDL assembly / Regulation of insulin secretion / channel-conductance-controlling ATPase / intracellularly ATP-gated chloride channel activity / positive regulation of enamel mineralization / Rap1 signalling / Ion homeostasis / RHO GTPases regulate CFTR trafficking / transepithelial water transport / 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 / Recruitment of NuMA to mitotic centrosomes / Anchoring of the basal body to the plasma membrane / AURKA Activation by TPX2 / RET signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / VEGFA-VEGFR2 Pathway / intracellular pH elevation / Regulation of PLK1 Activity at G2/M Transition / amelogenesis / PKA activation / Hedgehog 'off' state / MAPK6/MAPK4 signaling / GLI3 is processed to GLI3R by the proteasome / chloride channel inhibitor activity / multicellular organismal-level water homeostasis / water transport / chloride channel regulator activity / Golgi-associated vesicle membrane / bicarbonate transmembrane transporter activity / membrane hyperpolarization / bicarbonate transport / mesoderm formation / chloride transmembrane transporter activity / histone H1-4S35 kinase activity / cAMP-dependent protein kinase / positive regulation of triglyceride catabolic process / cAMP-dependent protein kinase activity / insulin secretion involved in cellular response to glucose stimulus / regulation of bicellular tight junction assembly / cAMP-dependent protein kinase complex / negative regulation of glycolytic process through fructose-6-phosphate / sperm capacitation / Mitochondrial protein degradation / regulation of osteoblast differentiation / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / protein kinase A regulatory subunit binding / 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 / RHOQ GTPase cycle / chloride channel activity / intracellular potassium ion homeostasis / ATPase-coupled transmembrane transporter activity / sperm flagellum / plasma membrane raft / axoneme / ABC-type transporter activity / postsynaptic modulation of chemical synaptic transmission / positive regulation of gluconeogenesis / cellular response to cAMP / protein serine/threonine/tyrosine kinase activity / 14-3-3 protein binding / cellular response to glucagon stimulus / positive regulation of phagocytosis / response to endoplasmic reticulum stress / negative regulation of TORC1 signaling / mRNA processing / acrosomal vesicle / regulation of proteasomal protein catabolic process / negative regulation of protein localization to chromatin / chloride transmembrane transport / cellular response to forskolin / Developmental Lineage of Pancreatic Ductal Cells / lipid droplet / neuromuscular junction / PDZ domain binding / clathrin-coated endocytic vesicle membrane / regulation of microtubule cytoskeleton organization / negative regulation of smoothened signaling pathway / positive regulation of cholesterol biosynthetic process / Late endosomal microautophagy / positive regulation of protein localization to plasma membrane / Defective CFTR causes cystic fibrosis / recycling endosome / transmembrane transport / ABC-family protein mediated transport / recycling endosome membrane / Chaperone Mediated Autophagy / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Aggrephagy / manganese ion binding
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: 9.0 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_47235.png

Downloads & links

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Map

FileDownload / File: emd_47235.map.gz / Format: CCP4 / Size: 325 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationDephosphorylated CFTR in complex with PKA-C (site II)
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)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.676 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.11543069 - 0.27211824
Average (Standard dev.)0.0027862503 (±0.021551242)
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 1

Fileemd_47235_half_map_1.map
Annotationhalf-map 1
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half-map 2

Fileemd_47235_half_map_2.map
Annotationhalf-map 2
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 CFTR in 1:1 complex with PKA-C (position II)

EntireName: dephosphorylated CFTR in 1:1 complex with PKA-C (position II)
Components
  • Complex: dephosphorylated CFTR in 1:1 complex with PKA-C (position II)
    • Protein or peptide: cAMP-dependent protein kinase catalytic subunit alpha
    • Protein or peptide: Cystic fibrosis transmembrane conductance regulator
    • Protein or peptide: Cystic fibrosis transmembrane conductance regulator

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Supramolecule #1: dephosphorylated CFTR in 1:1 complex with PKA-C (position II)

SupramoleculeName: dephosphorylated CFTR in 1:1 complex with PKA-C (position II)
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Bos taurus (domestic cattle)
Molecular weightTheoretical: 210 KDa

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Macromolecule #1: cAMP-dependent protein kinase catalytic subunit alpha

MacromoleculeName: cAMP-dependent protein kinase catalytic subunit alpha / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO / EC number: cAMP-dependent protein kinase
Source (natural)Organism: Bos taurus (domestic cattle)
Molecular weightTheoretical: 40.677652 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 AKRVKGRTWT LCGTPEYLAP EIILSKGYNK AVDWWALGVL IYEMAAGYPP FF ADQPIQI YEKIVSGKVR FPSHFSSDLK DLLRNLLQVD LTKRFGNLKN GVNDIKNHKW FATTDWIAIY QRKVEAPFIP KFK GPGDTS NFDDYEEEEI RVSINEKCGK EFSEF

UniProtKB: cAMP-dependent protein kinase catalytic subunit alpha

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Macromolecule #2: Cystic fibrosis transmembrane conductance regulator

MacromoleculeName: Cystic fibrosis transmembrane conductance regulator / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO / EC number: channel-conductance-controlling ATPase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 168.335453 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 AKILLLDEPS AHLDPVTYQI IRRTLKQAFA DCTVILCEHR IEAMLECQQF LVIEENKVRQ YDSIQKLLNE RSLFRQA IS PSDRVKLFPH RNSSKCKSKP QIAALKEETE EEVQDTRL

UniProtKB: Cystic fibrosis transmembrane conductance regulator

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Macromolecule #3: Cystic fibrosis transmembrane conductance regulator

MacromoleculeName: Cystic fibrosis transmembrane conductance regulator / type: protein_or_peptide / ID: 3 / Details: R domain of CFTR / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 1.635006 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)(UNK)(UNK)(UNK) (UNK)(UNK)(UNK)

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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: 52.0 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:

8516

Final reconstructionResolution.type: BY AUTHOR / Resolution: 9.0 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 14655
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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