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- EMDB-47260: PKD2 ion channel, F629S variant -

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Basic information

Entry
Database: EMDB / ID: EMD-47260
TitlePKD2 ion channel, F629S variant
Map dataEM Map PKD2 Variant F629S
Sample
  • Complex: PKD2 ion channel F629S variant protomer
    • Protein or peptide: Polycystin-2
  • Ligand: CALCIUM ION
KeywordsIon channel / TRP channel / polycystin / membrane protein
Function / homology
Function and homology information


detection of nodal flow / metanephric smooth muscle tissue development / metanephric cortex development / metanephric cortical collecting duct development / metanephric distal tubule development / polycystin complex / mesonephric tubule development / mesonephric duct development / metanephric part of ureteric bud development / renal tubule morphogenesis ...detection of nodal flow / metanephric smooth muscle tissue development / metanephric cortex development / metanephric cortical collecting duct development / metanephric distal tubule development / polycystin complex / mesonephric tubule development / mesonephric duct development / metanephric part of ureteric bud development / renal tubule morphogenesis / determination of liver left/right asymmetry / metanephric ascending thin limb development / metanephric mesenchyme development / metanephric S-shaped body morphogenesis / basal cortex / renal artery morphogenesis / HLH domain binding / calcium-induced calcium release activity / migrasome / cilium organization / VxPx cargo-targeting to cilium / detection of mechanical stimulus / muscle alpha-actinin binding / regulation of calcium ion import / voltage-gated monoatomic ion channel activity / placenta blood vessel development / cellular response to hydrostatic pressure / cellular response to fluid shear stress / cation channel complex / outward rectifier potassium channel activity / non-motile cilium / actinin binding / cellular response to osmotic stress / determination of left/right symmetry / : / voltage-gated monoatomic cation channel activity / neural tube development / voltage-gated sodium channel activity / aorta development / motile cilium / branching involved in ureteric bud morphogenesis / ciliary membrane / protein heterotetramerization / negative regulation of G1/S transition of mitotic cell cycle / spinal cord development / heart looping / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / cytoplasmic side of endoplasmic reticulum membrane / centrosome duplication / voltage-gated potassium channel activity / potassium channel activity / cell surface receptor signaling pathway via JAK-STAT / embryonic placenta development / voltage-gated calcium channel activity / monoatomic cation channel activity / transcription regulator inhibitor activity / cytoskeletal protein binding / release of sequestered calcium ion into cytosol / potassium ion transmembrane transport / sodium ion transmembrane transport / cellular response to calcium ion / basal plasma membrane / cytoplasmic vesicle membrane / cellular response to cAMP / lumenal side of endoplasmic reticulum membrane / cellular response to reactive oxygen species / protein tetramerization / phosphoprotein binding / establishment of localization in cell / liver development / calcium ion transmembrane transport / Wnt signaling pathway / intracellular calcium ion homeostasis / positive regulation of nitric oxide biosynthetic process / mitotic spindle / cell-cell junction / calcium ion transport / lamellipodium / regulation of cell population proliferation / heart development / ATPase binding / protein homotetramerization / basolateral plasma membrane / transmembrane transporter binding / cell surface receptor signaling pathway / regulation of cell cycle / cilium / ciliary basal body / signaling receptor binding / negative regulation of cell population proliferation / calcium ion binding / endoplasmic reticulum membrane / positive regulation of gene expression / endoplasmic reticulum / Golgi apparatus / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / extracellular exosome / identical protein binding / membrane
Similarity search - Function
Ferredoxin I 4Fe-4S cluster domain / : / Polycystic kidney disease type 2 protein / Polycystin domain / Polycystin domain / Polycystin cation channel, PKD1/PKD2 / Polycystin cation channel / Voltage-dependent channel domain superfamily / EF-hand calcium-binding domain profile. / EF-hand domain / EF-hand domain pair
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.76 Å
AuthorsEsarte Palomero O / DeCaen PG
Funding support United States, 5 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)R01 DK131118-01 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)R01 DK123463-01 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)(F32DK137477-01A1 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)TL1DK132769 United States
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)U2CDK129917 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2025
Title: Pathogenic variants in the polycystin pore helix cause distinct forms of channel dysfunction.
Authors: Orhi Esarte Palomero / Eduardo Guadarrama / Paul G DeCaen /
Abstract: PKD2 is a member of the polycystin subfamily of transient receptor potential (TRP) ion channel subunits which traffic and function in primary cilia organelle membranes. Millions of individuals carry ...PKD2 is a member of the polycystin subfamily of transient receptor potential (TRP) ion channel subunits which traffic and function in primary cilia organelle membranes. Millions of individuals carry pathogenic genetic variants in PKD2 that cause a life-threatening condition called autosomal dominant polycystic kidney disease (ADPKD). Although ADPKD is a common monogenetic disorder, there is no drug cure or available therapeutics which address the underlying channel dysregulation. Furthermore, the structural and mechanistic impacts of most disease-causing variants are uncharacterized. Using direct cilia electrophysiology, cryogenic electron microscopy (cryo-EM), and superresolution imaging, we have found mechanistic differences in channel dysregulation caused by three germline missense variants located in PKD2's pore helix 1. Variant C632R reduces protein thermal stability, resulting in impaired channel assembly and abolishes primary cilia trafficking. In contrast, variants F629S and R638C retain native cilia trafficking but exhibit gating defects. Cryo-EM structures (2.7 to 2.8 Å resolution) indicate loss of critical pore helix interactions which precipitate allosteric collapse of the channels inner gate. Results demonstrate how ADPKD-causing mutations cause mechanistically divergent and ranging impacts on PKD2 function, despite their shared structural proximity. These unexpected findings highlight the need for structural and biophysical characterization of polycystin variants, which will guide rational drug development of ADPKD therapeutics.
History
DepositionOct 9, 2024-
Header (metadata) releaseMar 12, 2025-
Map releaseMar 12, 2025-
UpdateSep 3, 2025-
Current statusSep 3, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_47260.png

Downloads & links

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Map

FileDownload / File: emd_47260.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationEM Map PKD2 Variant F629S
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.65 Å/pix.
x 400 pix.
= 259.52 Å		0.65 Å/pix.
x 400 pix.
= 259.52 Å		0.65 Å/pix.
x 400 pix.
= 259.52 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.6488 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.102
Minimum - Maximum-0.44219112 - 0.5949078
Average (Standard dev.)0.00036152132 (±0.020962054)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions400400400
Spacing400400400
CellA=B=C: 259.52002 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_47260_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: EM Half Map A PKD2 Variant F629S

Fileemd_47260_half_map_1.map
AnnotationEM Half Map A PKD2 Variant F629S
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: EM Half Map B PKD2 Variant F629S

Fileemd_47260_half_map_2.map
AnnotationEM Half Map B PKD2 Variant F629S
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : PKD2 ion channel F629S variant protomer

EntireName: PKD2 ion channel F629S variant protomer
Components
  • Complex: PKD2 ion channel F629S variant protomer
    • Protein or peptide: Polycystin-2
  • Ligand: CALCIUM ION

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Supramolecule #1: PKD2 ion channel F629S variant protomer

SupramoleculeName: PKD2 ion channel F629S variant protomer / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 339.6 KDa

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Macromolecule #1: Polycystin-2

MacromoleculeName: Polycystin-2 / type: protein_or_peptide / ID: 1
Details: PKD2 variant F629S (residues 52-793) was expressed with an N-terminal StrepII-MBP-TEV cleaved prior to macromolecular analysis
Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 85.043344 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GEIEMQRIRQ AAARDPPAGA AASPSPPLSS CSRQAWSRDN PGFEAEEEEE EVEGEEGGMV VEMDVEWRPG SRRSAASSAV SSVGARSRG LGGYHGAGHP SGRRRRREDQ GPPCPSPVGG GDPLHRHLPL EGQPPRVAWA ERLVRGLRGL WGTRLMEESS T NREKYLKS ...String:
GEIEMQRIRQ AAARDPPAGA AASPSPPLSS CSRQAWSRDN PGFEAEEEEE EVEGEEGGMV VEMDVEWRPG SRRSAASSAV SSVGARSRG LGGYHGAGHP SGRRRRREDQ GPPCPSPVGG GDPLHRHLPL EGQPPRVAWA ERLVRGLRGL WGTRLMEESS T NREKYLKS VLRELVTYLL FLIVLCILTY GMMSSNVYYY TRMMSQLFLD TPVSKTEKTN FKTLSSMEDF WKFTEGSLLD GL YWKMQPS NQTEADNRSF IFYENLLLGV PRIRQLRVRN GSCSIPQDLR DEIKECYDVY SVSSEDRAPF GPRNGTAWIY TSE KDLNGS SHWGIIATYS GAGYYLDLSR TREETAAQVA SLKKNVWLDR GTRATFIDFS VYNANINLFC VVRLLVEFPA TGGV IPSWQ FQPLKLIRYV TTFDFFLAAC EIIFCFFIFY YVVEEILEIR IHKLHYFRSF WNCLDVVIVV LSVVAIGINI YRTSN VEVL LQFLEDQNTF PNFEHLAYWQ IQFNNIAAVT VFFVWIKLFK FINFNRTMSQ LSTTMSRCAK DLFGFAIMFF IIFLAY AQL AYLVFGTQVD DFSTSQECIF TQFRIILGDI NFAEIEEANR VLGPIYFTTF VFFMFFILLN MFLAIINDTY SEVKSDL AQ QKAEMELSDL IRKGYHKALV KLKLKKNTVD DISESLRQGG GKLNFDELRQ DLKGKGHTDA EIEAIFTKYD QDGDQELT E HEHQQMRDDL EKEREDLDLD

UniProtKB: Polycystin-2

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Macromolecule #2: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 2 / Number of copies: 1 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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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

Concentration1.0 mg/mL
BufferpH: 7.4
Component:
ConcentrationFormulaName
150.0 mMNaClSodium Chloride
25.0 mMHEPES(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid)
1.0 mMCaCl2Calcium Chloride
1.0 mMTCEPtris(2-carboxyethyl)phosphine

Details: 25 mM HEPES-NaOH, 150 mM NaCl, 1 mM CaCl2, 1 mM TCEP
GridModel: Quantifoil R2/1 / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 20 sec. / Pretreatment - Atmosphere: AIR / Pretreatment - Pressure: 0.026000000000000002 kPa / Details: 15 mA
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 278 K / Instrument: LEICA EM GP
Details: Vitrification carried in air. Ethane temperature -183 C.
DetailsStabilized in amphipol A8-35. Monodisperse sample after gel filtration in a Superdex 200 column.

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Digitization - Dimensions - Width: 11520 pixel / Digitization - Dimensions - Height: 8184 pixel / Number grids imaged: 1 / Number real images: 9145 / Average electron dose: 60.0 e/Å2 / Details: 50 frame movie stacks. Super-resolution mode
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 2.4 µm / Nominal defocus min: 0.6 µm / Nominal magnification: 130000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1046126
Details: Denoised micrographs were blob picked (130-170 angstrom)
CTF correctionSoftware - Name: cryoSPARC (ver. 4.5) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: INSILICO MODEL / In silico model: Ab-initio reconstruction
Final reconstructionNumber classes used: 1 / Applied symmetry - Point group: C4 (4 fold cyclic) / Algorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.76 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.5)
Details: Final reconstruction performed with C4 symmetry imposed
Number images used: 215875
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.5)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.5)
Final 3D classificationNumber classes: 3 / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Source name: AlphaFold / Chain - Initial model type: in silico model
DetailsThe initial Alphafold model was fitted to the map using ChimeraX. Refinement was performed using ISOLDE and PHENIX.
RefinementSpace: REAL / Overall B value: 107.9
Output model

PDB-9dwq:
PKD2 ion channel, F629S variant

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