|Entry||Database: EMDB / ID: 9111|
|Title||Structural basis for cholesterol transport-like activity of the Hedgehog receptor Patched|
|Map data||PTCH1 monomer|
|Sample||Patched1 protein solubilized in amphipol:|
Protein patched homolog 1 / ligand
|Function / homology||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. ...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
|Source||Homo sapiens (human) / Mus musculus (house mouse)|
|Method||single particle reconstruction / cryo EM / 3.6 Å resolution|
|Authors||Zhang Y / Bulkley D / Xin Y / Roberts KJ / Asarnow DE / Sharma A / Myers BR / Cho W / Cheng Y / Beachy PA|
|Citation||Journal: 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 Report||PDB-ID: 6mg8|
SummaryFull reportAbout validation report
|Date||Deposition: Sep 13, 2018 / Header (metadata) release: Nov 28, 2018 / Map release: Nov 28, 2018 / Last update: Nov 28, 2018|
|Structure viewer||EM map: |
Downloads & links
|File||emd_9111.map.gz (map file in CCP4 format, 157217 KB)|
|Projections & slices|
Images are generated by Spider.
|Voxel size||X=Y=Z: 1.31 Å|
CCP4 map header:
-Entire Patched1 protein solubilized in amphipol
|Entire||Name: Patched1 protein solubilized in amphipol / Number of components: 3|
-Component #1: protein, Patched1 protein solubilized in amphipol
|Protein||Name: Patched1 protein solubilized in amphipol / Recombinant expression: No|
|Mass||Theoretical: 145.2 kDa|
|Source||Species: Homo sapiens (human)|
|Source (engineered)||Expression System: Homo sapiens (human) / Vector: BacMam / Cell of expression system: HEK293|
-Component #2: protein, Protein patched homolog 1
|Protein||Name: Protein patched homolog 1 / Number of Copies: 1 / Recombinant expression: No|
|Mass||Theoretical: 145.357844 kDa|
|Source||Species: Mus musculus (house mouse)|
|Source (engineered)||Expression System: Homo sapiens (human)|
-Component #3: ligand, UNKNOWN LIGAND
|Ligand||Name: UNKNOWN LIGAND / Number of Copies: 4 / Recombinant expression: No|
|Mass||Theoretical: 0.197236 kDa|
|Specimen||Specimen state: particle / Method: cryo EM|
|Sample solution||Specimen conc.: 0.3 mg/ml / pH: 7.4|
|Vitrification||Instrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Temperature: 23 K / Humidity: 100 %|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Imaging||Microscope: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 38 e/Å2 / Illumination mode: FLOOD BEAM|
|Lens||Cs: 2.7 mm / Imaging mode: BRIGHT FIELD|
|Specimen Holder||Model: OTHER|
|Camera||Detector: GATAN K2 SUMMIT (4k x 4k)|
|Image acquisition||Number of digital images: 5236|
|Processing||Method: single particle reconstruction / Applied symmetry: C1 (asymmetric) / Number of projections: 245725|
|3D reconstruction||Software: RELION / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF|
-Atomic model buiding
|Modeling #1||Refinement space: REAL|
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