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- EMDB-24113: Structure of TAX-4_R421W w/cGMP open state -

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Basic information

Entry
Database: EMDB / ID: EMD-24113
TitleStructure of TAX-4_R421W w/cGMP open state
Map data
Sample
  • Complex: Cyclic nucleotide-gated channel TAX-4 with an achromatopsia-associated missense mutation R421W
    • Protein or peptide: Cyclic nucleotide-gated cation channel
  • Ligand: CYCLIC GUANOSINE MONOPHOSPHATE
  • Ligand: 1-PALMITOYL-2-LINOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: 1,2-DILAUROYL-SN-GLYCERO-3-PHOSPHATE
Keywordsion channel / blindness-associated mutation / achromatopsia / phototransduction / TRANSPORT PROTEIN
Function / homology
Function and homology information


detection of carbon dioxide / detection of chemical stimulus involved in sensory perception / Activation of the phototransduction cascade / Inactivation, recovery and regulation of the phototransduction cascade / VxPx cargo-targeting to cilium / ciliary inversin compartment / thermosensory behavior / positive regulation of growth rate / olfactory behavior / intracellular cyclic nucleotide activated cation channel complex ...detection of carbon dioxide / detection of chemical stimulus involved in sensory perception / Activation of the phototransduction cascade / Inactivation, recovery and regulation of the phototransduction cascade / VxPx cargo-targeting to cilium / ciliary inversin compartment / thermosensory behavior / positive regulation of growth rate / olfactory behavior / intracellular cyclic nucleotide activated cation channel complex / intracellularly cGMP-activated cation channel activity / aerotaxis / chemosensory behavior / multicellular organismal reproductive process / intracellularly cAMP-activated cation channel activity / G protein-coupled receptor signaling pathway coupled to cGMP nucleotide second messenger / cation channel complex / response to oxygen levels / thermotaxis / non-motile cilium / regulation of neuron differentiation / regulation of axon extension / negative regulation of cGMP-mediated signaling / monoatomic cation transmembrane transport / phototransduction / cGMP binding / voltage-gated potassium channel activity / response to hyperoxia / neuron projection morphogenesis / calcium-mediated signaling / chemotaxis / dendrite / positive regulation of gene expression / protein-containing complex binding / positive regulation of transcription by RNA polymerase II / identical protein binding / membrane / plasma membrane
Similarity search - Function
Cyclic nucleotide-gated channel, C-terminal leucine zipper domain / C-terminal leucine zipper domain of cyclic nucleotide-gated channels / : / Potassium channel, voltage-dependent, EAG/ELK/ERG / Cyclic nucleotide-binding domain signature 2. / Cyclic nucleotide-binding domain signature 1. / Cyclic nucleotide-binding, conserved site / Cyclic nucleotide-monophosphate binding domain / Cyclic nucleotide-binding domain / cAMP/cGMP binding motif profile. ...Cyclic nucleotide-gated channel, C-terminal leucine zipper domain / C-terminal leucine zipper domain of cyclic nucleotide-gated channels / : / Potassium channel, voltage-dependent, EAG/ELK/ERG / Cyclic nucleotide-binding domain signature 2. / Cyclic nucleotide-binding domain signature 1. / Cyclic nucleotide-binding, conserved site / Cyclic nucleotide-monophosphate binding domain / Cyclic nucleotide-binding domain / cAMP/cGMP binding motif profile. / Cyclic nucleotide-binding domain / Cyclic nucleotide-binding domain superfamily / RmlC-like jelly roll fold / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
Cyclic nucleotide-gated channel
Similarity search - Component
Biological speciesCaenorhabditis elegans (invertebrata)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsZheng X / Li H
Funding support United States, 2 items
OrganizationGrant numberCountry
National Institutes of Health/National Eye Institute (NIH/NEI)R01EY027800 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM085234 United States
CitationJournal: Commun Biol / Year: 2022
Title: Structural and functional characterization of an achromatopsia-associated mutation in a phototransduction channel.
Authors: Xiangdong Zheng / Huan Li / Zhengshan Hu / Deyuan Su / Jian Yang /
Abstract: Numerous missense mutations in cyclic nucleotide-gated (CNG) channels cause achromatopsia and retinitis pigmentosa, but the underlying pathogenic mechanisms are often unclear. We investigated the ...Numerous missense mutations in cyclic nucleotide-gated (CNG) channels cause achromatopsia and retinitis pigmentosa, but the underlying pathogenic mechanisms are often unclear. We investigated the structural basis and molecular/cellular effects of R410W, an achromatopsia-associated, presumed loss-of-function mutation in human CNGA3. Cryo-EM structures of the Caenorhabditis elegans TAX-4 CNG channel carrying the analogous mutation, R421W, show that most apo channels are open. R421, located in the gating ring, interacts with the S4 segment in the closed state. R421W disrupts this interaction, destabilizes the closed state, and stabilizes the open state. CNGA3_R410W/CNGB3 and TAX4_R421W channels are spontaneously active without cGMP and induce cell death, suggesting cone degeneration triggered by spontaneous CNG channel activity as a possible cause of achromatopsia. Our study sheds new light on CNG channel allosteric gating, provides an impetus for a reevaluation of reported loss-of-function CNG channel missense disease mutations, and has implications for mutation-specific treatment of retinopathy.
History
DepositionMay 27, 2021-
Header (metadata) releaseMar 16, 2022-
Map releaseMar 16, 2022-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.45
  • Imaged by UCSF Chimera
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  • Surface view colored by cylindrical radius
  • Surface level: 0.45
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7n15
  • Surface level: 0.45
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_24113.png

Downloads & links

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Map

FileDownload / File: emd_24113.map.gz / Format: CCP4 / Size: 98.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 296 pix.
= 245.68 Å		0.83 Å/pix.
x 296 pix.
= 245.68 Å		0.83 Å/pix.
x 296 pix.
= 245.68 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.83 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.45 / Movie #1: 0.45
Minimum - Maximum-4.5760627 - 6.881638
Average (Standard dev.)0.0012924122 (±0.17974165)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions296296296
Spacing296296296
CellA=B=C: 245.68 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.830.830.83
M x/y/z296296296
origin x/y/z0.0000.0000.000
length x/y/z245.680245.680245.680
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ450450450
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS296296296
D min/max/mean-4.5766.8820.001

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Supplemental data

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Sample components

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Entire : Cyclic nucleotide-gated channel TAX-4 with an achromatopsia-assoc...

EntireName: Cyclic nucleotide-gated channel TAX-4 with an achromatopsia-associated missense mutation R421W
Components
  • Complex: Cyclic nucleotide-gated channel TAX-4 with an achromatopsia-associated missense mutation R421W
    • Protein or peptide: Cyclic nucleotide-gated cation channel
  • Ligand: CYCLIC GUANOSINE MONOPHOSPHATE
  • Ligand: 1-PALMITOYL-2-LINOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
  • Ligand: 1,2-DILAUROYL-SN-GLYCERO-3-PHOSPHATE

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Supramolecule #1: Cyclic nucleotide-gated channel TAX-4 with an achromatopsia-assoc...

SupramoleculeName: Cyclic nucleotide-gated channel TAX-4 with an achromatopsia-associated missense mutation R421W
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Caenorhabditis elegans (invertebrata)

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Macromolecule #1: Cyclic nucleotide-gated cation channel

MacromoleculeName: Cyclic nucleotide-gated cation channel / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Caenorhabditis elegans (invertebrata)
Molecular weightTheoretical: 84.334914 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GGGGSMSTAE PAPDPTNPST SGLAPTTNGI GSPPPTASAA TKFSILTKFL RRKNQVHTTT AQQNEFMQKY MPNGNSNAVQ PAATGGQPA SSDGGSAIEV PPPKESYAVR IRKYLANYTQ DPSTDNFYYW TCVVTVAYIY NLLFVIARQV FNDLIGPSSQ S LCRFYNGT ...String:
GGGGSMSTAE PAPDPTNPST SGLAPTTNGI GSPPPTASAA TKFSILTKFL RRKNQVHTTT AQQNEFMQKY MPNGNSNAVQ PAATGGQPA SSDGGSAIEV PPPKESYAVR IRKYLANYTQ DPSTDNFYYW TCVVTVAYIY NLLFVIARQV FNDLIGPSSQ S LCRFYNGT LNSTTQVECT YNMLTNMKEM PTYSQYPDLG WSKYWHFRML WVFFDLLMDC VYLIDTFLNY RMGYMDQGLV VR EAEKVTK AYWQSKQYRI DGISLIPLDY ILGWPIPYIN WRGLPILRLN RLIRYKRVRN CLERTETRSS MPNAFRVVVV VWY IVIIIH WNACLYFWIS EWIGLGTDAW VYGHLNKQSL PDDITDTLLR RYVYSFYWST LILTTIGEVP SPVRNIEYAF VTLD LMCGV LIFATIVGNV GSMISNMSAA WTEFQNKMDG IKQYMELRKV SKQLEIRVIK WFDYLWTNKQ SLSDQQVLKV LPDKL QAEI AMQVHFETLR KVRIFQDCEA GLLAELVLKL QLQVFSPGDF ICKKGDIGRE MYIVKRGRLQ VVDDDGKKVF VTLQEG SVF GELSILNIAG SKNGNRRTAN VRSVGYTDLF VLSKTDLWNA LREYPDARKL LLAKGREILK KDNLLDENAP EEQKTVE EI AEHLNNAVKV LQTRMARLIV EHSSTEGKLM KRIEMLEKHL SRYKALARRQ KTMHGVSIDG GDISTDGVDE RVRPPRLR Q TKTIDLPTGT ESESLLK

UniProtKB: Cyclic nucleotide-gated channel

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Macromolecule #2: CYCLIC GUANOSINE MONOPHOSPHATE

MacromoleculeName: CYCLIC GUANOSINE MONOPHOSPHATE / type: ligand / ID: 2 / Number of copies: 4 / Formula: PCG
Molecular weightTheoretical: 345.205 Da
Chemical component information

ChemComp-PCG:
CYCLIC GUANOSINE MONOPHOSPHATE

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Macromolecule #3: 1-PALMITOYL-2-LINOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE

MacromoleculeName: 1-PALMITOYL-2-LINOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 3 / Number of copies: 20 / Formula: CPL
Molecular weightTheoretical: 758.06 Da
Chemical component information

ChemComp-CPL:
1-PALMITOYL-2-LINOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / phospholipid*YM

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Macromolecule #4: 1,2-DILAUROYL-SN-GLYCERO-3-PHOSPHATE

MacromoleculeName: 1,2-DILAUROYL-SN-GLYCERO-3-PHOSPHATE / type: ligand / ID: 4 / Number of copies: 4 / Formula: PX2
Molecular weightTheoretical: 535.671 Da
Chemical component information

ChemComp-PX2:
1,2-DILAUROYL-SN-GLYCERO-3-PHOSPHATE

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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

BufferpH: 7.4
GridModel: C-flat-1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 69.7 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: OTHER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 3988515
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6wek

Final reconstructionApplied symmetry - Point group: C4 (4 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 284615
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 2.9)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 2.9)
Final 3D classificationSoftware - Name: cryoSPARC

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Atomic model buiding 1

Initial modelPDB ID:

6wek


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: FLEXIBLE FIT
Output model

PDB-7n15:
Structure of TAX-4_R421W w/cGMP open state

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