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- PDB-7rhq: Cryo-EM structure of Xenopus Patched-1 in complex with GAS1 and S... -

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Basic information

Entry
Database: PDB / ID: 7rhq
TitleCryo-EM structure of Xenopus Patched-1 in complex with GAS1 and Sonic Hedgehog
Components
  • Growth arrest-specific protein 1
  • Patched-1
  • Sonic hedgehog protein N-productSonic hedgehog protein
KeywordsMEMBRANE PROTEIN / GPCR / complex
Function / homology
Function and homology information


: / Formation of lateral plate mesoderm / positive regulation of skeletal muscle cell proliferation / right lung development / left lung development / primary prostatic bud elongation / regulation of mesenchymal cell proliferation involved in prostate gland development / mesenchymal smoothened signaling pathway involved in prostate gland development / positive regulation of sclerotome development / tracheoesophageal septum formation ...: / Formation of lateral plate mesoderm / positive regulation of skeletal muscle cell proliferation / right lung development / left lung development / primary prostatic bud elongation / regulation of mesenchymal cell proliferation involved in prostate gland development / mesenchymal smoothened signaling pathway involved in prostate gland development / positive regulation of sclerotome development / tracheoesophageal septum formation / negative regulation of ureter smooth muscle cell differentiation / positive regulation of ureter smooth muscle cell differentiation / negative regulation of kidney smooth muscle cell differentiation / positive regulation of kidney smooth muscle cell differentiation / morphogen activity / regulation of odontogenesis / positive regulation of mesenchymal cell proliferation involved in ureter development / polarity specification of anterior/posterior axis / trunk neural crest cell migration / hedgehog receptor activity / hindgut morphogenesis / striated muscle tissue development / negative regulation of alpha-beta T cell differentiation / regulation of glial cell proliferation / regulation of prostatic bud formation / metanephric mesenchymal cell proliferation involved in metanephros development / formation of anatomical boundary / lung epithelium development / positive regulation of striated muscle cell differentiation / ventral midline development / trachea morphogenesis / cholesterol-protein transferase activity / bud outgrowth involved in lung branching / HHAT G278V doesn't palmitoylate Hh-Np / telencephalon regionalization / epithelial-mesenchymal cell signaling / : / laminin-1 binding / Ligand-receptor interactions / salivary gland cavitation / negative regulation of cholesterol efflux / determination of left/right asymmetry in lateral mesoderm / spinal cord dorsal/ventral patterning / regulation of ER to Golgi vesicle-mediated transport / negative regulation of mesenchymal cell apoptotic process / positive regulation of cerebellar granule cell precursor proliferation / cell development / negative regulation of T cell differentiation in thymus / spinal cord motor neuron differentiation / positive regulation of T cell differentiation in thymus / intermediate filament organization / cerebellar granule cell precursor proliferation / mesenchymal cell apoptotic process / embryonic skeletal system development / prostate gland development / establishment of epithelial cell polarity / limb bud formation / lung lobe morphogenesis / Activation of SMO / skeletal muscle fiber differentiation / thalamus development / embryonic foregut morphogenesis / patched binding / embryonic digestive tract morphogenesis / somite development / hindbrain development / negative thymic T cell selection / positive regulation of skeletal muscle tissue development / ectoderm development / epithelial cell proliferation involved in salivary gland morphogenesis / animal organ formation / neuron fate commitment / dorsal/ventral neural tube patterning / stem cell development / mesenchymal cell proliferation involved in lung development / negative regulation of dopaminergic neuron differentiation / skeletal muscle cell proliferation / positive regulation of immature T cell proliferation in thymus / oligodendrocyte development / lymphoid progenitor cell differentiation / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / smooth muscle tissue development / male genitalia development / positive regulation of astrocyte differentiation / regulation of stem cell proliferation / pattern specification process / artery development / self proteolysis / epithelial cell proliferation involved in prostate gland development / branching involved in salivary gland morphogenesis / positive regulation of epithelial cell proliferation involved in prostate gland development / embryonic pattern specification / Release of Hh-Np from the secreting cell / regulation of proteolysis / positive thymic T cell selection / lung-associated mesenchyme development / Formation of axial mesoderm / dopaminergic neuron differentiation / metanephros development / glycosaminoglycan binding
Similarity search - Function
Growth arrest-specific protein 1 / GDNF/GAS1 / GDNF/GAS1 domain / GDNF/GAS1 domain / Transmembrane receptor, patched / Hedgehog, N-terminal signalling domain / Hedgehog protein / Hedgehog protein, Hint domain / Hint module / Hedgehog amino-terminal signalling domain ...Growth arrest-specific protein 1 / GDNF/GAS1 / GDNF/GAS1 domain / GDNF/GAS1 domain / Transmembrane receptor, patched / Hedgehog, N-terminal signalling domain / Hedgehog protein / Hedgehog protein, Hint domain / Hint module / Hedgehog amino-terminal signalling domain / Hedgehog signalling/DD-peptidase zinc-binding domain superfamily / Sterol-sensing domain of SREBP cleavage-activation / Protein patched/dispatched / Patched family / Sterol-sensing domain (SSD) profile. / Sterol-sensing domain / Hint domain C-terminal / Hint (Hedgehog/Intein) domain C-terminal region / Intein N-terminal splicing region / Intein N-terminal splicing motif profile. / Hint domain N-terminal / Hint (Hedgehog/Intein) domain N-terminal region / Hint domain superfamily
Similarity search - Domain/homology
CHOLESTEROL / PALMITIC ACID / CHOLESTEROL HEMISUCCINATE / Growth arrest-specific protein 1 / Sonic hedgehog protein / Patched-1
Similarity search - Component
Biological speciesXenopus laevis (African clawed frog)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.53 Å
AuthorsHuang, P. / Lian, T. / Wierbowski, B. / Garcia-Linares, S. / Jiang, J. / Salic, A.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM122920 United States
CitationJournal: Dev Cell / Year: 2022
Title: Structural basis for catalyzed assembly of the Sonic hedgehog-Patched1 signaling complex.
Authors: Pengxiang Huang / Bradley M Wierbowski / Tengfei Lian / Charlene Chan / Sara García-Linares / Jiansen Jiang / Adrian Salic /
Abstract: The dually lipidated Sonic hedgehog (SHH) morphogen signals through the tumor suppressor membrane protein Patched1 (PTCH1) to activate the Hedgehog pathway, which is fundamental in development and ...The dually lipidated Sonic hedgehog (SHH) morphogen signals through the tumor suppressor membrane protein Patched1 (PTCH1) to activate the Hedgehog pathway, which is fundamental in development and cancer. SHH engagement with PTCH1 requires the GAS1 coreceptor, but the mechanism is unknown. We demonstrate a unique role for GAS1, catalyzing SHH-PTCH1 complex assembly in vertebrate cells by direct SHH transfer from the extracellular SCUBE2 carrier to PTCH1. Structure of the GAS1-SHH-PTCH1 transition state identifies how GAS1 recognizes the SHH palmitate and cholesterol modifications in modular fashion and how it facilitates lipid-dependent SHH handoff to PTCH1. Structure-guided experiments elucidate SHH movement from SCUBE2 to PTCH1, explain disease mutations, and demonstrate that SHH-induced PTCH1 dimerization causes its internalization from the cell surface. These results define how the signaling-competent SHH-PTCH1 complex assembles, the key step triggering the Hedgehog pathway, and provide a paradigm for understanding morphogen reception and its regulation.
History
DepositionJul 18, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 2, 2022Provider: repository / Type: Initial release
Revision 1.1Mar 9, 2022Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Mar 23, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

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Assembly

Deposited unit
A: Patched-1
C: Sonic hedgehog protein N-product
G: Growth arrest-specific protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)188,92615
Polymers185,5483
Non-polymers3,37812
Water0
1


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

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Components

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Protein , 3 types, 3 molecules ACG

#1: Protein Patched-1 /


Mass: 134622.391 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Gene: ptch1.S, Ptc1, ptch1, XELAEV_18010170mg / Production host: Insecta environmental sample (insect) / References: UniProt: Q98SW6
#2: Protein Sonic hedgehog protein N-product / Sonic hedgehog protein / ShhN / Shh N-terminal processed signaling domains / ShhNp


Mass: 21378.926 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SHH / Production host: Homo sapiens (human) / References: UniProt: Q15465
#3: Protein Growth arrest-specific protein 1 / GAS-1


Mass: 29546.764 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GAS1 / Production host: Homo sapiens (human) / References: UniProt: P54826

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Sugars , 2 types, 5 molecules

#4: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#7: 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 / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6
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

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Non-polymers , 5 types, 7 molecules

#5: Chemical ChemComp-CLR / CHOLESTEROL / Cholesterol


Mass: 386.654 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H46O
#6: Chemical ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H50O4
#8: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#9: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Ca
#10: Chemical ChemComp-PLM / PALMITIC ACID / Palmitic acid


Mass: 256.424 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H32O2

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Details

Has ligand of interestN

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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: Patched Hedgehog GAS1 complex / Type: COMPLEX / Entity ID: #1, #3 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding 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: SPOT SCAN
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm / C2 aperture diameter: 100 µm
Image recordingElectron dose: 71 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: NONE
3D reconstructionResolution: 3.53 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 54175 / Symmetry type: POINT

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