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- EMDB-30958: Cryo-EM structure of hDisp1NNN-ShhN -

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Basic information

Entry
Database: EMDB / ID: EMD-30958
TitleCryo-EM structure of hDisp1NNN-ShhN
Map data
Sample
  • Complex: hDisp1NNN-ShhN
    • Complex: ShhN
      • Protein or peptide: Sonic hedgehog protein
    • Complex: hDisp1NNN
      • Protein or peptide: Protein dispatched homolog 1
  • Ligand: ZINC ION
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
Function / homology
Function and homology information


patched ligand maturation / 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 ...patched ligand maturation / 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 / 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 / diaphragm development / 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 / 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 / cerebellar granule cell precursor proliferation / intermediate filament organization / mesenchymal cell apoptotic process / embryonic skeletal system development / limb bud formation / lung lobe morphogenesis / prostate gland development / Activation of SMO / skeletal muscle fiber differentiation / establishment of epithelial cell polarity / patched binding / embryonic foregut morphogenesis / thalamus development / embryonic digestive tract morphogenesis / somite development / hindbrain development / positive regulation of skeletal muscle tissue development / epithelial cell proliferation involved in salivary gland morphogenesis / ectoderm development / 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 / negative thymic T cell selection / 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 / regulation of stem cell proliferation / pattern specification process / artery development / positive regulation of astrocyte differentiation / epithelial cell proliferation involved in prostate gland development / self proteolysis / peptide transport / 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 / lung-associated mesenchyme development / Formation of axial mesoderm / regulation of proteolysis / peptide transmembrane transporter activity / dopaminergic neuron differentiation / metanephros development / positive thymic T cell selection
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 / Protein patched/dispatched / Patched family / Sterol-sensing domain (SSD) profile. / Sterol-sensing domain ...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 / 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
Sonic hedgehog protein / Protein dispatched homolog 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 4.07 Å
AuthorsLi W / Wang L / Gong X
Funding support China, 2 items
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, 2021-
Header (metadata) releaseDec 8, 2021-
Map releaseDec 8, 2021-
UpdateDec 8, 2021-
Current statusDec 8, 2021Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.024
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.024
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7e2i
  • Surface level: 0.024
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_30958.png

Downloads & links

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Map

FileDownload / File: emd_30958.map.gz / Format: CCP4 / Size: 18.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.114 Å
Density
Contour LevelBy AUTHOR: 0.021 / Movie #1: 0.024
Minimum - Maximum-0.079936765 - 0.1243633
Average (Standard dev.)0.0005742672 (±0.005547726)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions168168168
Spacing168168168
CellA=B=C: 187.152 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.1141.1141.114
M x/y/z168168168
origin x/y/z0.0000.0000.000
length x/y/z187.152187.152187.152
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS168168168
D min/max/mean-0.0800.1240.001

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Supplemental data

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Sample components

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Entire : hDisp1NNN-ShhN

EntireName: hDisp1NNN-ShhN
Components
  • Complex: hDisp1NNN-ShhN
    • Complex: ShhN
      • Protein or peptide: Sonic hedgehog protein
    • Complex: hDisp1NNN
      • Protein or peptide: Protein dispatched homolog 1
  • Ligand: ZINC ION
  • Ligand: CHOLESTEROL HEMISUCCINATE
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose

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Supramolecule #1: hDisp1NNN-ShhN

SupramoleculeName: hDisp1NNN-ShhN / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Molecular weightTheoretical: 150 KDa

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Supramolecule #2: ShhN

SupramoleculeName: ShhN / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Mammalian expression vector EGFP-MCS-pcDNA3.1 (others)

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Supramolecule #3: hDisp1NNN

SupramoleculeName: hDisp1NNN / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Mammalian expression vector EGFP-MCS-pcDNA3.1 (others)

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Macromolecule #1: Sonic hedgehog protein

MacromoleculeName: Sonic hedgehog protein / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 49.676172 KDa
Recombinant expressionOrganism: Mammalian expression vector Flag-EGFP-MCS-pcDNA3.1 (others)
SequenceString: MLLLARCLLL VLVSSLLVCS GLACGPGRGF GKRRHPKKLT PLAYKQFIPN VAEKTLGASG RYEGKISRNS ERFKELTPNY NPDIIFKDE ENTGADRLMT QRCKDKLNAL AISVMNQWPG VKLRVTEGWD EDGHHSEESL HYEGRAVDIT TSDRDRSKYG M LARLAVEA ...String:
MLLLARCLLL VLVSSLLVCS GLACGPGRGF GKRRHPKKLT PLAYKQFIPN VAEKTLGASG RYEGKISRNS ERFKELTPNY NPDIIFKDE ENTGADRLMT QRCKDKLNAL AISVMNQWPG VKLRVTEGWD EDGHHSEESL HYEGRAVDIT TSDRDRSKYG M LARLAVEA GFDWVYYESK AHIHCSVKAE NSVAAKSGGC FPGSATVHLE QGGTKLVKDL SPGDRVLAAD DQGRLLYSDF LT FLDRDDG AKKVFYVIET REPRERLLLT AAHLLFVAPH NDSATGEPEA SSGSGPPSGG ALGPRALFAS RVRPGQRVYV VAE RDGDRR LLPAAVHSVT LSEEAAGAYA PLTAQGTILI NRVLASCYAV IEEHSWAHRA FAPFRLAHAL LAALAPARTD RGGD SGGGD RGGGGGRVAL TAPGAADAPG AGATAGIHWY SQLLYQIGTW LLDSEALHPL GMAVKSS

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Macromolecule #2: Protein dispatched homolog 1

MacromoleculeName: Protein dispatched homolog 1 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 171.110094 KDa
Recombinant expressionOrganism: Mammalian expression vector Flag-EGFP-MCS-pcDNA3.1 (others)
SequenceString: MAMSNGNNDF VVLSNSSIAT SAANPSPLTP CDGDHAAQQL TPKEATRTKV SPNGCLQLNG TVKSSFLPLD NQRMPQMLPQ CCHPCPYHH PLTSHSSHQE CHPEAGPAAP SALASCCMQP HSEYSASLCP NHSPVYQTTC CLQPSPSFCL HHPWPDHFQH Q PVQQHIAN ...String:
MAMSNGNNDF VVLSNSSIAT SAANPSPLTP CDGDHAAQQL TPKEATRTKV SPNGCLQLNG TVKSSFLPLD NQRMPQMLPQ CCHPCPYHH PLTSHSSHQE CHPEAGPAAP SALASCCMQP HSEYSASLCP NHSPVYQTTC CLQPSPSFCL HHPWPDHFQH Q PVQQHIAN IRPSRPFKLP KSYAALIADW PVVVLGMCTM FIVVCALVGV LVPELPDFSD PLLGFEPRGT AIGQRLVTWN NM VKNTGYK ATLANYPFKY ADEQAKSHRD DRWSDDHYER EKREVDWNFH KDSFFCDVPS DRYSRVVFTS SGGETLWNLP AIK SMCNVD NSRIRSHPQF GDLCQRTTAA SCCPSWTLGN YIAILNNRSS CQKIVERDVS HTLKLLRTCA KHYQNGTLGP DCWD MAARR KDQLKCTNVP RKCTKYNAVY QILHYLVDKD FMTPKTADYA TPALKYSMLF SPTEKGESMM NIYLDNFENW NSSDG VTTI TGIEFGIKHS LFQDYLLMDT VYPAIAIVIV LLVMCVYTKS MFITLMTMFA IISSLIVSYF LYRVVFHFEF FPFMNL TAL IILVGIGANN AFVLCDVWNY TKFDKPHAET SETVSITLQH AALSMFVTSF TTAAAFYANY VSNITAIRCF GVYAGTA IL VNYVLMVTWL PAVVVLHERY LLNIFTCFKK PQQQIYDNKS CWTVACQKCH KVLFAISEAS RIFFEKVLPC IVIKFRYL W LFWFLALTVG GAYIVCINPK MKLPSLELSE FQVFRSSHPF ERYDAEYKKL FMFERVHHGE ELHMPITVIW GVSPEDNGN PLNPKSKGKL TLDSSFNIAS PASQAWILHF CQKLRNQTFF YQTDEQDFTS CFIETFKQWM ENQDCDEPAL YPCCSHWSFP YKQEIFELC IKRAIMELER STGYHLDSKT PGPRFDINDT IRAVVLEFQS TYLFTLAYEK MHQFYKEVDS WISSELSSAP E GLSNGWFV SNLEFYDLQD SLSDGTLIAM GLSVAVAFSV MLLTTWNIII SLYAIISIAG TIFVTVGSLV LLGWELNVLE SV TISVAVG LSVNFAVHYG VAYRLAPDPD REGKVIFSLS RVGSAMAMAA LTTFVAGAMM MPSTVLAYTQ LGTFMMLIMC ISW AFATFF FQCMCRCLGP QGTCGQIPLP KKLQCSAFSH ALSTSPSDKG QSKTHTINAY HLDPRGPKSE LEHEFYELEP LASH SCTAP EKTTYEETHI CSEFFNSQAK NLGMPVHAAY NSELSKSTES DAGSALLQPP LEQHTVCHFF SLNQRCSCPD AYKHL NYGP HSCQQMGDCL CHQCSPTTSS FVQIQNGVAP LKATHQAVEG FVHPITHIHH CPCLQGRVKP AGMQNSLPRN FFLHPV QHI QAQEKIGKTN VHSLQRSIEE HLPKMAEPSS FVCRSTGSLL KTCCDPENKQ RELCKNRDVS NLESSGGTEN KAGGKVE LS LSQTDASVNS EHFNQNEPKV LFNHLMGEAG CRSCPNNSQS CGRIVRVKCN SVDCQMPNME ANVPAVLTHS ELSGESLL I KTL

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Macromolecule #3: ZINC ION

MacromoleculeName: ZINC ION / type: ligand / ID: 3 / Number of copies: 1 / Formula: ZN
Molecular weightTheoretical: 65.409 Da

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Macromolecule #4: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 4 / Number of copies: 7 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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Macromolecule #5: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 5 / Number of copies: 4 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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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

Concentration7.5 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE / Chamber humidity: 100 %

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: SUPER-RESOLUTION / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 4.07 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 173169

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