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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 / morphogen activity / 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 / morphogen activity / 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 / hindgut morphogenesis / regulation of odontogenesis / positive regulation of mesenchymal cell proliferation involved in ureter development / trunk neural crest cell migration / Formation of lateral plate mesoderm / polarity specification of anterior/posterior axis / striated muscle tissue development / negative regulation of alpha-beta T cell differentiation / regulation of glial cell proliferation / regulation of prostatic bud formation / ventral midline development / metanephric mesenchymal cell proliferation involved in metanephros development / formation of anatomical boundary / lung epithelium development / cholesterol-protein transferase activity / positive regulation of striated muscle cell differentiation / trachea morphogenesis / bud outgrowth involved in lung branching / HHAT G278V doesn't palmitoylate Hh-Np / diaphragm development / telencephalon regionalization / epithelial-mesenchymal cell signaling / Ligand-receptor interactions / laminin-1 binding / limb bud formation / lung lobe morphogenesis / negative regulation of cholesterol efflux / salivary gland cavitation / spinal cord dorsal/ventral patterning / negative regulation of mesenchymal cell apoptotic process / embryonic digestive tract morphogenesis / determination of left/right asymmetry in lateral mesoderm / epithelial cell proliferation involved in salivary gland morphogenesis / positive regulation of cerebellar granule cell precursor proliferation / negative regulation of T cell differentiation in thymus / spinal cord motor neuron differentiation / cell development / positive regulation of T cell differentiation in thymus / Activation of SMO / mesenchymal cell proliferation involved in lung development / cerebellar granule cell precursor proliferation / intermediate filament organization / prostate gland development / lymphoid progenitor cell differentiation / embryonic skeletal system development / establishment of epithelial cell polarity / skeletal muscle fiber differentiation / somite development / mesenchymal cell apoptotic process / patched binding / neuron fate commitment / animal organ formation / embryonic foregut morphogenesis / hindbrain development / ectoderm development / positive regulation of skeletal muscle tissue development / stem cell development / embryonic pattern specification / branching involved in salivary gland morphogenesis / thalamus development / negative regulation of dopaminergic neuron differentiation / skeletal muscle cell proliferation / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / positive regulation of immature T cell proliferation in thymus / dorsal/ventral neural tube patterning / negative thymic T cell selection / smooth muscle tissue development / self proteolysis / pattern specification process / male genitalia development / artery development / lung-associated mesenchyme development / positive regulation of astrocyte differentiation / oligodendrocyte development / regulation of stem cell proliferation / epithelial cell proliferation involved in prostate gland development / positive regulation of epithelial cell proliferation involved in prostate gland development / Release of Hh-Np from the secreting cell / dopaminergic neuron differentiation / intein-mediated protein splicing / glycosaminoglycan binding / regulation of proteolysis / Formation of axial mesoderm / metanephric collecting duct development / 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 ...: / 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)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.11 Å/pix.
x 168 pix.
= 187.152 Å		1.11 Å/pix.
x 168 pix.
= 187.152 Å		1.11 Å/pix.
x 168 pix.
= 187.152 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.114 Å
Density

Histogram

Histogram (log scale)
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

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

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Image processing

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

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