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- PDB-7e2i: Cryo-EM structure of hDisp1NNN-ShhN -

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Basic information

Entry
Database: PDB / ID: 7e2i
TitleCryo-EM structure of hDisp1NNN-ShhN
Components
  • Protein dispatched homolog 1
  • Sonic hedgehog protein
KeywordsLIPID TRANSPORT / membrane protein
Function / homology
Function and homology information


patched ligand maturation / 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 ...patched ligand maturation / 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 / Formation of lateral plate mesoderm / epithelial-mesenchymal cell signaling / polarity specification of anterior/posterior axis / ventral midline development / metanephric mesenchymal cell proliferation involved in metanephros development / cholesterol-protein transferase activity / diaphragm development / HHAT G278V doesn't palmitoylate Hh-Np / Ligand-receptor interactions / laminin-1 binding / determination of left/right asymmetry in lateral mesoderm / negative regulation of cholesterol efflux / positive regulation of T cell differentiation in thymus / cerebellar granule cell precursor proliferation / cell development / prostate gland development / stem cell development / patched binding / Developmental Lineage of Multipotent Pancreatic Progenitor Cells / somite development / hindbrain development / neuron fate commitment / Activation of SMO / pattern specification process / self proteolysis / smooth muscle tissue development / negative thymic T cell selection / negative regulation of dopaminergic neuron differentiation / male genitalia development / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / dopaminergic neuron differentiation / positive regulation of immature T cell proliferation in thymus / lymphoid progenitor cell differentiation / Release of Hh-Np from the secreting cell / glycosaminoglycan binding / embryonic pattern specification / positive regulation of alpha-beta T cell differentiation / Formation of axial mesoderm / positive thymic T cell selection / metanephros development / intein-mediated protein splicing / metanephric collecting duct development / positive regulation of smoothened signaling pathway / dorsal/ventral pattern formation / regulation of protein localization to nucleus / embryonic limb morphogenesis / peptide transport / cell fate specification / Class B/2 (Secretin family receptors) / determination of left/right symmetry / molecular carrier activity / neural crest cell migration / embryonic digit morphogenesis / smoothened signaling pathway / branching involved in ureteric bud morphogenesis / branching involved in blood vessel morphogenesis / branching morphogenesis of an epithelial tube / midbrain development / forebrain development / regulation of protein secretion / heart looping / oligodendrocyte differentiation / neuroblast proliferation / androgen metabolic process / protein autoprocessing / positive regulation of cell division / regulation of proteolysis / negative regulation of cell differentiation / vasculogenesis / lung development / thymus development / negative regulation of cell migration / axon guidance / central nervous system development / apoptotic signaling pathway / Hh mutants are degraded by ERAD / Hedgehog ligand biogenesis / Hedgehog 'on' state / T cell differentiation in thymus / peptidase activity / cell-cell signaling / regulation of cell population proliferation / heart development / extracellular matrix / regulation of gene expression / endopeptidase activity / basolateral plasma membrane / Hydrolases; Acting on ester bonds / membrane raft / endoplasmic reticulum lumen
Similarity search - Function
: / 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 / Membrane transport protein MMPL domain / MMPL family ...: / 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 / Membrane transport protein MMPL domain / MMPL family / : / 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 HEMISUCCINATE / Sonic hedgehog protein / Protein dispatched homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.07 Å
AuthorsLi, W. / Wang, L. / Gong, X.
Funding support China, 2items
OrganizationGrant numberCountry
Other government China
Other government China
CitationJournal: Nat Commun / Year: 2021
Title: Structural insights into proteolytic activation of the human Dispatched1 transporter for Hedgehog morphogen release.
Authors: Wanqiu Li / Linlin Wang / Bradley M Wierbowski / Mo Lu / Feitong Dong / Wenchen Liu / Sisi Li / Peiyi Wang / Adrian Salic / Xin Gong /
Abstract: The membrane protein Dispatched (Disp), which belongs to the RND family of small molecule transporters, is essential for Hedgehog (Hh) signaling, by catalyzing the extracellular release of palmitate- ...The membrane protein Dispatched (Disp), which belongs to the RND family of small molecule transporters, is essential for Hedgehog (Hh) signaling, by catalyzing the extracellular release of palmitate- and cholesterol-modified Hh ligands from producing cells. Disp function requires Furin-mediated proteolytic cleavage of its extracellular domain, but how this activates Disp remains obscure. Here, we employ cryo-electron microscopy to determine atomic structures of human Disp1 (hDisp1), before and after cleavage, and in complex with lipid-modified Sonic hedgehog (Shh) ligand. These structures, together with biochemical data, reveal that proteolytic cleavage opens the extracellular domain of hDisp1, removing steric hindrance to Shh binding. Structure-guided functional experiments demonstrate the role of hDisp1-Shh interactions in ligand release. Our results clarify the mechanisms of hDisp1 activation and Shh morphogen release, and highlight how a unique proteolytic cleavage event enabled acquisition of a protein substrate by a member of a family of small molecule transporters.
History
DepositionFeb 5, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 8, 2021Provider: repository / Type: Initial release
Revision 1.0Dec 8, 2021Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Dec 8, 2021Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 8, 2021Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.0Dec 8, 2021Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Dec 8, 2021Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Nov 13, 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
Revision 1.2Jun 18, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jun 18, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

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Assembly

Deposited unit
G: Sonic hedgehog protein
D: Protein dispatched homolog 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)225,14414
Polymers220,7862
Non-polymers4,35712
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area2340 Å2
ΔGint0 kcal/mol
Surface area51940 Å2

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Components

#1: Protein Sonic hedgehog protein / SHH / HHG-1 / Shh unprocessed N-terminal signaling and C-terminal autoprocessing domains / ShhNC


Mass: 49676.172 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SHH
Production host: Mammalian expression vector Flag-EGFP-MCS-pcDNA3.1 (others)
References: UniProt: Q15465
#2: Protein Protein dispatched homolog 1


Mass: 171110.094 Da / Num. of mol.: 1 / Mutation: D572N,D573N,D1051N
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: DISP1, DISPA
Production host: Mammalian expression vector Flag-EGFP-MCS-pcDNA3.1 (others)
References: UniProt: Q96F81
#3: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#4: Chemical
ChemComp-Y01 / CHOLESTEROL HEMISUCCINATE


Mass: 486.726 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C31H50O4
#5: 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.: 4 / Source method: obtained synthetically / Formula: C8H15NO6 / Feature type: SUBJECT OF INVESTIGATION
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
Has ligand of interestY
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

Component
IDNameTypeEntity IDParent-IDSource
1hDisp1NNN-ShhNCOMPLEX#1-#20RECOMBINANT
2ShhNCOMPLEX#11RECOMBINANT
3hDisp1NNNCOMPLEX#21RECOMBINANT
Molecular weightValue: 0.15 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Mammalian expression vector EGFP-MCS-pcDNA3.1 (others)2021194
33Mammalian expression vector EGFP-MCS-pcDNA3.1 (others)2021194
Buffer solutionpH: 8
SpecimenConc.: 7.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE / Humidity: 100 %

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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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD
Image recordingElectron dose: 50 e/Å2 / Detector mode: SUPER-RESOLUTION / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.16_3549: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 4.07 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 173169 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0068806
ELECTRON MICROSCOPYf_angle_d0.76912015
ELECTRON MICROSCOPYf_dihedral_angle_d9.1295212
ELECTRON MICROSCOPYf_chiral_restr0.0541387
ELECTRON MICROSCOPYf_plane_restr0.0051476

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