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- EMDB-9111: Structural basis for cholesterol transport-like activity of the H... -

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Basic information

Entry
Database: EMDB / ID: 9111
TitleStructural basis for cholesterol transport-like activity of the Hedgehog receptor Patched
Map dataPTCH1 monomer
SamplePatched1 protein solubilized in amphipol:
Protein patched homolog 1 / ligand
Function / homologyTransmembrane receptor, patched / Hedgehog 'on' state / Hedgehog 'off' state / Ligand-receptor interactions / Activation of SMO / Sterol-sensing domain / Patched family / Sterol-sensing domain of SREBP cleavage-activation / Protein patched/dispatched / Sterol-sensing domain (SSD) profile. ...Transmembrane receptor, patched / Hedgehog 'on' state / Hedgehog 'off' state / Ligand-receptor interactions / Activation of SMO / Sterol-sensing domain / Patched family / Sterol-sensing domain of SREBP cleavage-activation / Protein patched/dispatched / Sterol-sensing domain (SSD) profile. / neural plate axis specification / hedgehog receptor activity / response to chlorate / cell proliferation involved in metanephros development / smoothened signaling pathway involved in dorsal/ventral neural tube patterning / cell differentiation involved in kidney development / neural tube patterning / smoothened binding / epidermal cell fate specification / hedgehog family protein binding / hindlimb morphogenesis / neural tube formation / spinal cord motor neuron differentiation / mammary gland duct morphogenesis / dorsal/ventral neural tube patterning / patched binding / limb morphogenesis / somite development / cellular response to cholesterol / negative regulation of smoothened signaling pathway / negative regulation of cell division / keratinocyte proliferation / negative regulation of multicellular organism growth / positive regulation of cholesterol efflux / dorsal/ventral pattern formation / pharyngeal system development / positive regulation of epidermal cell differentiation / mammary gland epithelial cell differentiation / cell fate determination / commissural neuron axon guidance / mammary gland development / smoothened signaling pathway / prostate gland development / regulation of smoothened signaling pathway / embryonic organ development / pattern specification process / cholesterol binding / embryonic limb morphogenesis / negative regulation of osteoblast differentiation / regulation of mitotic cell cycle / regulation of growth / epidermis development / branching involved in ureteric bud morphogenesis / negative regulation of epithelial cell proliferation / dendritic growth cone / heart morphogenesis / protein processing / axonal growth cone / cilium / cyclin binding / protein localization to plasma membrane / response to retinoic acid / regulation of protein localization / liver regeneration / response to mechanical stimulus / neural tube closure / animal organ morphogenesis / caveola / brain development / midbody / negative regulation of DNA-binding transcription factor activity / glucose homeostasis / in utero embryonic development / regulation of cell population proliferation / response to estradiol / heparin binding / postsynaptic density / protein-containing complex binding / response to drug / intracellular membrane-bounded organelle / negative regulation of cell population proliferation / negative regulation of transcription, DNA-templated / positive regulation of transcription, DNA-templated / integral component of plasma membrane / Golgi apparatus / negative regulation of transcription by RNA polymerase II / perinuclear region of cytoplasm / signal transduction / zinc ion binding / extracellular region / plasma membrane / nucleus / Protein patched homolog 1
Function and homology information
SourceHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / 3.6 Å resolution
AuthorsZhang Y / Bulkley D / Xin Y / Roberts KJ / Asarnow DE / Sharma A / Myers BR / Cho W / Cheng Y / Beachy PA
CitationJournal: Cell / Year: 2018
Title: Structural Basis for Cholesterol Transport-like Activity of the Hedgehog Receptor Patched.
Authors: Yunxiao Zhang / David P Bulkley / Yao Xin / Kelsey J Roberts / Daniel E Asarnow / Ashutosh Sharma / Benjamin R Myers / Wonhwa Cho / Yifan Cheng / Philip A Beachy
Abstract: Hedgehog protein signals mediate tissue patterning and maintenance by binding to and inactivating their common receptor Patched, a 12-transmembrane protein that otherwise would suppress the activity ...Hedgehog protein signals mediate tissue patterning and maintenance by binding to and inactivating their common receptor Patched, a 12-transmembrane protein that otherwise would suppress the activity of the 7-transmembrane protein Smoothened. Loss of Patched function, the most common cause of basal cell carcinoma, permits unregulated activation of Smoothened and of the Hedgehog pathway. A cryo-EM structure of the Patched protein reveals striking transmembrane domain similarities to prokaryotic RND transporters. A central hydrophobic conduit with cholesterol-like contents courses through the extracellular domain and resembles that used by other RND proteins to transport substrates, suggesting Patched activity in cholesterol transport. Cholesterol activity in the inner leaflet of the plasma membrane is reduced by PTCH1 expression but rapidly restored by Hedgehog stimulation, suggesting that PTCH1 regulates Smoothened by controlling cholesterol availability.
Validation ReportPDB-ID: 6mg8

SummaryFull reportAbout validation report
DateDeposition: Sep 13, 2018 / Header (metadata) release: Nov 28, 2018 / Map release: Nov 28, 2018 / Last update: Nov 28, 2018

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.04
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.04
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: : PDB-6mg8
  • Surface level: 0.04
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

Fileemd_9111.map.gz (map file in CCP4 format, 157217 KB)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
340 pix
1.31 Å/pix.
= 445.4 Å
340 pix
1.31 Å/pix.
= 445.4 Å
340 pix
1.31 Å/pix.
= 445.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.31 Å
Density
Contour Level:0.04 (by author), 0.04 (movie #1):
Minimum - Maximum-0.16621485 - 0.2775069
Average (Standard dev.)0.000110226545 (0.0026982878)
Details

EMDB XML:

Space Group Number1
Map Geometry
Axis orderXYZ
Dimensions340340340
Origin0.00.00.0
Limit339.0339.0339.0
Spacing340340340
CellA=B=C: 445.4 Å
α=β=γ: 90.0 deg.

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.311.311.31
M x/y/z340340340
origin x/y/z0.0000.0000.000
length x/y/z445.400445.400445.400
α/β/γ90.00090.00090.000
start NX/NY/NZ
NX/NY/NZ
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS340340340
D min/max/mean-0.1660.2780.000

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Supplemental data

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Sample components

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Entire Patched1 protein solubilized in amphipol

EntireName: Patched1 protein solubilized in amphipol / Number of components: 3

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Component #1: protein, Patched1 protein solubilized in amphipol

ProteinName: Patched1 protein solubilized in amphipol / Recombinant expression: No
MassTheoretical: 145.2 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Homo sapiens (human) / Vector: BacMam / Cell of expression system: HEK293

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Component #2: protein, Protein patched homolog 1

ProteinName: Protein patched homolog 1 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 145.357844 kDa
SourceSpecies: Mus musculus (house mouse)
Source (engineered)Expression System: Homo sapiens (human)

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Component #3: ligand, UNKNOWN LIGAND

LigandName: UNKNOWN LIGAND / Number of Copies: 4 / Recombinant expression: No
MassTheoretical: 0.197236 kDa

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Experimental details

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Sample preparation

SpecimenSpecimen state: particle / Method: cryo EM
Sample solutionSpecimen conc.: 0.3 mg/ml / pH: 7.4
VitrificationInstrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Temperature: 23 K / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 38 e/Å2 / Illumination mode: FLOOD BEAM
LensCs: 2.7 mm / Imaging mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: GATAN K2 SUMMIT (4k x 4k)

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Image acquisition

Image acquisitionNumber of digital images: 5236

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Image processing

ProcessingMethod: single particle reconstruction / Applied symmetry: C1 (asymmetric) / Number of projections: 245725
3D reconstructionSoftware: RELION / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF
FSC plot
(resolution estimation)

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Atomic model buiding

Modeling #1Refinement space: REAL
Output model

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