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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-product
KeywordsMEMBRANE PROTEIN / GPCR / complex
Function / homology
Function and homology information


regulation of nodal signaling pathway / positive regulation of sclerotome development / 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 / hedgehog receptor activity ...regulation of nodal signaling pathway / positive regulation of sclerotome development / 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 / hedgehog receptor activity / Formation of lateral plate mesoderm / epithelial-mesenchymal cell signaling / polarity specification of anterior/posterior axis / smoothened binding / ventral midline development / metanephric mesenchymal cell proliferation involved in metanephros development / hedgehog family protein binding / cholesterol-protein transferase activity / HHAT G278V doesn't palmitoylate Hh-Np / negative thymic T cell selection / Ligand-receptor interactions / laminin-1 binding / positive regulation of T cell differentiation in thymus / stem cell development / cerebellar granule cell precursor proliferation / determination of left/right asymmetry in lateral mesoderm / negative regulation of cholesterol efflux / lymphoid progenitor cell differentiation / regulation of ER to Golgi vesicle-mediated transport / cell development / somite development / prostate gland development / male genitalia development / hindbrain development / patched binding / neuron fate commitment / Developmental Lineage of Multipotent Pancreatic Progenitor Cells / smooth muscle tissue development / positive regulation of immature T cell proliferation in thymus / pattern specification process / Activation of SMO / self proteolysis / negative regulation of dopaminergic neuron differentiation / dopaminergic neuron differentiation / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / metanephros development / embryonic limb morphogenesis / androgen metabolic process / embryonic pattern specification / Release of Hh-Np from the secreting cell / negative regulation of mitotic cell cycle / positive regulation of smoothened signaling pathway / glycosaminoglycan binding / positive thymic T cell selection / positive regulation of alpha-beta T cell differentiation / dorsal/ventral pattern formation / neural crest cell migration / oxysterol binding / Formation of axial mesoderm / intein-mediated protein splicing / metanephric collecting duct development / regulation of smoothened signaling pathway / branching involved in blood vessel morphogenesis / cell fate specification / smoothened signaling pathway / regulation of protein localization to nucleus / branching involved in ureteric bud morphogenesis / oligodendrocyte differentiation / negative regulation of protein processing / Class B/2 (Secretin family receptors) / forebrain development / embryonic digit morphogenesis / branching morphogenesis of an epithelial tube / midbrain development / neuroblast proliferation / heart looping / protein autoprocessing / positive regulation of cell division / cellular response to vascular endothelial growth factor stimulus / cell fate commitment / regulation of proteolysis / lung development / vasculogenesis / developmental growth / negative regulation of cell differentiation / thymus development / side of membrane / T cell differentiation in thymus / axon guidance / negative regulation of cell migration / apoptotic signaling pathway / negative regulation of smoothened signaling pathway / central nervous system development / Hh mutants are degraded by ERAD / Hedgehog ligand biogenesis / Hedgehog 'on' state / heart development / regulation of gene expression / regulation of cell population proliferation / peptidase activity
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 ...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 / 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 S homeolog
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
Revision 1.3Oct 23, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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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
Water00
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 / 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


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


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


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

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Details

Has ligand of interestN
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: 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 FIELD / 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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