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- EMDB-24466: Cryo-EM structure of Xenopus Patched-1 in complex with GAS1 and S... -

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Entry
Database: EMDB / ID: EMD-24466
TitleCryo-EM structure of Xenopus Patched-1 in complex with GAS1 and Sonic Hedgehog
Map data
Sample
  • Complex: Patched Hedgehog GAS1 complex
    • Protein or peptide: Patched-1
    • Protein or peptide: Growth arrest-specific protein 1
  • Protein or peptide: Sonic hedgehog protein N-product
  • Ligand: CHOLESTEROL
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: ZINC ION
  • Ligand: CALCIUM ION
  • Ligand: PALMITIC ACID
KeywordsGPCR / complex / MEMBRANE PROTEIN
Function / homology
Function and homology information


regulation of nodal signaling pathway / positive regulation of skeletal muscle cell proliferation / right lung development / left lung development / primary prostatic bud elongation / : / 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 ...regulation of nodal signaling pathway / positive regulation of skeletal muscle cell proliferation / right lung development / left lung development / primary prostatic bud elongation / : / 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 / hedgehog receptor activity / trunk neural crest cell migration / Formation of lateral plate mesoderm / hindgut morphogenesis / polarity specification of anterior/posterior axis / negative regulation of alpha-beta T cell differentiation / regulation of prostatic bud formation / formation of anatomical boundary / smoothened binding / positive regulation of striated muscle cell differentiation / regulation of glial cell proliferation / metanephric mesenchymal cell proliferation involved in metanephros development / ventral midline development / trachea morphogenesis / hedgehog family protein binding / cholesterol-protein transferase activity / HHAT G278V doesn't palmitoylate Hh-Np / telencephalon regionalization / bud outgrowth involved in lung branching / epithelial-mesenchymal cell signaling / Ligand-receptor interactions / laminin-1 binding / lung epithelium development / negative regulation of cholesterol efflux / salivary gland cavitation / spinal cord dorsal/ventral patterning / negative regulation of mesenchymal cell apoptotic process / determination of left/right asymmetry in lateral mesoderm / regulation of ER to Golgi vesicle-mediated transport / spinal cord motor neuron differentiation / negative regulation of T cell differentiation in thymus / cell development / establishment of epithelial cell polarity / positive regulation of T cell differentiation in thymus / skeletal muscle cell proliferation / prostate gland development / intermediate filament organization / limb bud formation / embryonic skeletal system development / stem cell development / skeletal muscle fiber differentiation / positive regulation of cerebellar granule cell precursor proliferation / animal organ formation / mesenchymal cell apoptotic process / patched binding / embryonic digestive tract morphogenesis / somite development / hindbrain development / positive regulation of skeletal muscle tissue development / ectoderm development / embryonic foregut morphogenesis / epithelial cell proliferation involved in salivary gland morphogenesis / cerebellar granule cell precursor proliferation / mesenchymal cell proliferation involved in lung development / neuron fate commitment / negative regulation of dopaminergic neuron differentiation / Activation of SMO / positive regulation of immature T cell proliferation in thymus / self proteolysis / smooth muscle tissue development / dorsal/ventral neural tube patterning / lung lobe morphogenesis / artery development / lymphoid progenitor cell differentiation / Release of Hh-Np from the secreting cell / positive regulation of astrocyte differentiation / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / regulation of stem cell proliferation / positive regulation of epithelial cell proliferation involved in prostate gland development / negative thymic T cell selection / pattern specification process / male genitalia development / branching involved in salivary gland morphogenesis / embryonic pattern specification / epithelial cell proliferation involved in prostate gland development / lung-associated mesenchyme development / intein-mediated protein splicing / glycosaminoglycan binding / oxysterol binding / Formation of axial mesoderm / dopaminergic neuron differentiation / metanephros development / thalamus development / Developmental Lineage of Pancreatic Acinar Cells
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 / Hint domain C-terminal / Hint (Hedgehog/Intein) domain C-terminal region / Sterol-sensing domain (SSD) profile. / Sterol-sensing domain / 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
Growth arrest-specific protein 1 / Sonic hedgehog protein / Patched 1 S homeolog
Similarity search - Component
Biological speciesHomo sapiens (human) / Xenopus laevis (African clawed frog)
Methodsingle 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, 1 items
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, 2021-
Header (metadata) releaseMar 2, 2022-
Map releaseMar 2, 2022-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.03
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.03
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7rhq
  • Surface level: 0.03
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_24466.png

Downloads & links

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Map

FileDownload / File: emd_24466.map.gz / Format: CCP4 / Size: 52.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 240 pix.
= 254.4 Å		1.06 Å/pix.
x 240 pix.
= 254.4 Å		1.06 Å/pix.
x 240 pix.
= 254.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.06 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.03 / Movie #1: 0.03
Minimum - Maximum-0.22365619 - 0.35638633
Average (Standard dev.)0.00000689173 (±0.0065497756)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions240240240
Spacing240240240
CellA=B=C: 254.4 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.061.061.06
M x/y/z240240240
origin x/y/z0.0000.0000.000
length x/y/z254.400254.400254.400
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ450450450
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS240240240
D min/max/mean-0.2240.3560.000

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Supplemental data

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Sample components

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Entire : Patched Hedgehog GAS1 complex

EntireName: Patched Hedgehog GAS1 complex
Components
  • Complex: Patched Hedgehog GAS1 complex
    • Protein or peptide: Patched-1
    • Protein or peptide: Growth arrest-specific protein 1
  • Protein or peptide: Sonic hedgehog protein N-product
  • Ligand: CHOLESTEROL
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: ZINC ION
  • Ligand: CALCIUM ION
  • Ligand: PALMITIC ACID

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Supramolecule #1: Patched Hedgehog GAS1 complex

SupramoleculeName: Patched Hedgehog GAS1 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1, #3
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Patched-1

MacromoleculeName: Patched-1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Xenopus laevis (African clawed frog)
Molecular weightTheoretical: 134.622391 KDa
Recombinant expressionOrganism: Insecta environmental sample (insect)
SequenceString: MASAACAAEL GASGEAAAQP RVVRRRGRSR RVAPPDHDYL QRPSYCDANF ALQQISEGKA IGRKAPLWLR AFFQRQLFKL GCYIQKNCG KFLVVGLLIF GAFAVGLRAA NLETNVEELW VEVGGRVSRE LDYTRQKIGE EAMFNPQLMI QTPLEDGANV L TTEALLQH ...String:
MASAACAAEL GASGEAAAQP RVVRRRGRSR RVAPPDHDYL QRPSYCDANF ALQQISEGKA IGRKAPLWLR AFFQRQLFKL GCYIQKNCG KFLVVGLLIF GAFAVGLRAA NLETNVEELW VEVGGRVSRE LDYTRQKIGE EAMFNPQLMI QTPLEDGANV L TTEALLQH LHSALEATKV QVYMYNKPWK LEELCFKSGE LITEAVYVSQ IIDSMYPCLI ITPLDCFWEG AKLQSGMAYL PG KDILQWT NFDPLELLEE LKKGKLHIDI WEEMINKAEV GHGYMDRPCL NPSDKNCPYT APNKNSTKPV DVSLILSGGC YGL SKKYMH WQEELIIGGT VKNASGQIVS ALALQTMFQL MTPKQMYEHF KGHEVVSHMN WNEDKAAAIL EAWQRTYVQV VHQS VPQNS SQKVLPFTTT TLDDILKSFS DVSVIRVASG YLLMLAYACL TMLRWDCAKS QGAVGLAGVL LVALSVAAGL GLCSL IGIS FNAATTQVLP FLALGVGVDD VFLLAHAFSE TGQNKRIPFE DRTGECLKRT GASVALTSIS NVTAFFMAAL IPIPAL RAF SLQAAVVVVF NFAMVLLIFP AILSMDLYRR EVRRLDIFCC FSSPCVSRVI QIEPQAYTDN NDNTRYSLPP TYSSHSF AH ETQITMQSTV QLRTEYDPRT QLYYTTAQPR SEISVQPAAS TPQDVSGQTP ESTSSTRDLI SQFSVHGGSM QCTPDSKW T LSSFAEKHYA PFLLKPKTKV AVILGFLALL SVSLYGTTRV RDGLDLTDIV PRETREYDFI ATQFKYFSFY HMYVVTQKA DYPRAQRLLY ELHKSFVGVR YVLLEGNKQL PKMWLHYFRD WLQGLQDTFD HEWEAGKITR NDYRNASDDA VLAYKLLIQT GNSDKPINL NQLTKQRLVD ADGIIQPNAF YIYLTAWVSN DPVAYAASQA NIRPHPPEWL HDKADDRPET RTIRAAEPIE Y VQFPFYLN GLRETSDFVE AIEKVRAICN NYTSLGVSSY PNGYPFLFWE QYISLRHWLL LSISVVLACT FLVCALFLLN PW TAGIIVM VLALMTVELF GMMGLIGIKL SAVPVVILIA SVGIGVEFTV HVALAFLTAV GDKNRRAVLA LEHMFAPVLD GAV STLLGV LMLAGSEFDF IVRYFFAVLA ILTLLGVLNG LVLLPVLLSF FGPYPEVSPT NGSSSPAAAH HHHHHHHEDQ VDPR LIDGK

UniProtKB: Patched 1 S homeolog

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Macromolecule #2: Sonic hedgehog protein N-product

MacromoleculeName: Sonic hedgehog protein N-product / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 21.378926 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: CGPGRGFGKR RHPKKLTPLA YKQFIPNVAE KTLGASGRYE GKISRNSERF KELTPNYNPD IIFKDEENTG ADRLMTQRCK DKLNALAIS VMNQWPGVKL RVTEGWDEGG TEDQVDPRLI DGKSGGDGHH SEESLHYEGR AVDITTSDRD RSKYGMLARL A VEAGFDWV ...String:
CGPGRGFGKR RHPKKLTPLA YKQFIPNVAE KTLGASGRYE GKISRNSERF KELTPNYNPD IIFKDEENTG ADRLMTQRCK DKLNALAIS VMNQWPGVKL RVTEGWDEGG TEDQVDPRLI DGKSGGDGHH SEESLHYEGR AVDITTSDRD RSKYGMLARL A VEAGFDWV YYESKAHIHC SVKAENSVAA KSGG

UniProtKB: Sonic hedgehog protein

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Macromolecule #3: Growth arrest-specific protein 1

MacromoleculeName: Growth arrest-specific protein 1 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 29.546764 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: GPGSLAHGRR LICWQALLQC QGEPECSYAY NQYAEACAPV LAQHGGGDAP GAAAAAFPAS AASFSSRWRC PSHCISALIQ LNHTRRGPA LEDCDCAQDE NCKSTKRAIE PCLPRTSGGG AGGPGAGGVM GCTEARRRCD RDSRCNLALS RYLTYCGKVF N GLRCTDEC ...String:
GPGSLAHGRR LICWQALLQC QGEPECSYAY NQYAEACAPV LAQHGGGDAP GAAAAAFPAS AASFSSRWRC PSHCISALIQ LNHTRRGPA LEDCDCAQDE NCKSTKRAIE PCLPRTSGGG AGGPGAGGVM GCTEARRRCD RDSRCNLALS RYLTYCGKVF N GLRCTDEC RTVIEDMLAM PKAALLNDCV CDGLERPICE SVKENMARLC FGAELGNGPG SSGSDGGLDD YYDEDYDDEQ RT GGAGGEQ PLDDDDGVPH PPRPGSGAAA SGGRGDLPYG PGRRS

UniProtKB: Growth arrest-specific protein 1

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Macromolecule #5: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 5 / Number of copies: 2 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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Macromolecule #6: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 6 / Number of copies: 1 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #7: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 7 / Number of copies: 2 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #8: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 8 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #9: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 9 / Number of copies: 2 / Formula: CA
Molecular weightTheoretical: 40.078 Da

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Macromolecule #10: PALMITIC ACID

MacromoleculeName: PALMITIC ACID / type: ligand / ID: 10 / Number of copies: 1 / Formula: PLM
Molecular weightTheoretical: 256.424 Da
Chemical component information

ChemComp-PLM:
PALMITIC ACID

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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: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Average electron dose: 71.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 100.0 µm / Illumination mode: SPOT SCAN / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.53 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 54175
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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