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- PDB-6wb8: Cryo-EM structure of PKD2 C331S disease variant -

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Basic information

Entry
Database: PDB / ID: 6wb8
TitleCryo-EM structure of PKD2 C331S disease variant
ComponentsPolycystin-2
KeywordsTRANSPORT PROTEIN / PKD2
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 / placenta blood vessel development / renal artery morphogenesis / HLH domain binding / VxPx cargo-targeting to cilium / cilium organization / migrasome / neural tube development / cellular response to fluid shear stress / muscle alpha-actinin binding / regulation of calcium ion import / calcium-induced calcium release activity / detection of mechanical stimulus / determination of left/right symmetry / voltage-gated monoatomic ion channel activity / embryonic placenta development / cellular response to hydrostatic pressure / aorta development / cation channel complex / branching involved in ureteric bud morphogenesis / non-motile cilium / outward rectifier potassium channel activity / motile cilium / actinin binding / cellular response to osmotic stress / negative regulation of G1/S transition of mitotic cell cycle / voltage-gated sodium channel activity / heart looping / spinal cord development / ciliary membrane / voltage-gated monoatomic cation channel activity / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / protein heterotetramerization / cytoplasmic side of endoplasmic reticulum membrane / potassium channel activity / voltage-gated potassium channel activity / centrosome duplication / transcription regulator inhibitor activity / cell surface receptor signaling pathway via JAK-STAT / voltage-gated calcium channel activity / release of sequestered calcium ion into cytosol / monoatomic cation channel activity / cytoskeletal protein binding / cellular response to calcium ion / cellular response to cAMP / liver development / potassium ion transmembrane transport / cytoplasmic vesicle membrane / basal plasma membrane / sodium ion transmembrane transport / lumenal side of endoplasmic reticulum membrane / cellular response to reactive oxygen species / protein tetramerization / phosphoprotein binding / Wnt signaling pathway / mitotic spindle / positive regulation of nitric oxide biosynthetic process / calcium ion transmembrane transport / heart development / calcium ion transport / transmembrane transport / cell-cell junction / cilium / regulation of cell population proliferation / lamellipodium / ATPase binding / ciliary basal body / protein homotetramerization / basolateral plasma membrane / transmembrane transporter binding / regulation of cell cycle / cell surface receptor signaling pathway / negative regulation of cell population proliferation / signaling receptor binding / positive regulation of gene expression / calcium ion binding / endoplasmic reticulum membrane / Golgi apparatus / endoplasmic reticulum / positive regulation of transcription by RNA polymerase II / protein homodimerization activity / extracellular exosome / membrane / identical protein binding / plasma membrane / cytoplasm
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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.24 Å
AuthorsCao, E. / Wang, J. / Decaen, P.G.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Disease (NIH/NIDDK)R01 DK110575 United States
CitationJournal: Proc Natl Acad Sci U S A / Year: 2020
Title: Molecular dysregulation of ciliary polycystin-2 channels caused by variants in the TOP domain.
Authors: Thuy N Vien / Jinliang Wang / Leo C T Ng / Erhu Cao / Paul G DeCaen /
Abstract: Genetic variants in which encodes for the polycystin-2 ion channel are responsible for many clinical cases of autosomal dominant polycystic kidney disease (ADPKD). Despite our strong understanding ...Genetic variants in which encodes for the polycystin-2 ion channel are responsible for many clinical cases of autosomal dominant polycystic kidney disease (ADPKD). Despite our strong understanding of the genetic basis of ADPKD, we do not know how most variants impact channel function. Polycystin-2 is found in organelle membranes, including the primary cilium-an antennae-like structure on the luminal side of the collecting duct. In this study, we focus on the structural and mechanistic regulation of polycystin-2 by its TOP domain-a site with unknown function that is commonly altered by missense variants. We use direct cilia electrophysiology, cryogenic electron microscopy, and superresolution imaging to determine that variants of the TOP domain finger 1 motif destabilizes the channel structure and impairs channel opening without altering cilia localization and channel assembly. Our findings support the channelopathy classification of variants associated with ADPKD, where polycystin-2 channel dysregulation in the primary cilia may contribute to cystogenesis.
History
DepositionMar 26, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 22, 2020Provider: repository / Type: Initial release
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Revision 1.1May 6, 2020Group: Database references / Category: citation / citation_author
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Revision 1.4Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
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Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.5Oct 30, 2024Group: Data collection / Database references / Structure summary
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Structure visualization

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Assembly

Deposited unit
A: Polycystin-2
B: Polycystin-2
C: Polycystin-2
D: Polycystin-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)348,72316
Polymers346,0684
Non-polymers2,65412
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Polycystin-2 / PC2 / Autosomal dominant polycystic kidney disease type II protein / Polycystic kidney disease 2 ...PC2 / Autosomal dominant polycystic kidney disease type II protein / Polycystic kidney disease 2 protein / Polycystwin / R48321 / Transient receptor potential cation channel subfamily P member 2


Mass: 86517.031 Da / Num. of mol.: 4 / Mutation: C331S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PKD2, TRPP2 / Production host: Homo sapiens (human) / Strain (production host): HEK293S GnTi- / References: UniProt: Q13563
#2: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 12
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
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: PKD2 / Type: CELL / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human) / Strain: HEK293S
Buffer solutionpH: 7.4
SpecimenConc.: 2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: DARK FIELD
Image recordingElectron dose: 1 e/Å2 / Film or detector model: GATAN K2 IS (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.10.1_2155: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.24 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 74302 / Symmetry type: POINT
Atomic model buildingB value: 100 / Protocol: OTHER / Space: REAL
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.01115288
ELECTRON MICROSCOPYf_angle_d0.89520836
ELECTRON MICROSCOPYf_dihedral_angle_d11.30911704
ELECTRON MICROSCOPYf_chiral_restr0.0512428
ELECTRON MICROSCOPYf_plane_restr0.0052568

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