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- EMDB-23837: Human Hedgehog acyltransferase (HHAT) in complex with a palmitoyl... -
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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-23837 | |||||||||
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Title | Human Hedgehog acyltransferase (HHAT) in complex with a palmitoylated Hedgehog peptide product and a Fab antibody fragment | |||||||||
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Function / homology | ![]() N-terminal peptidyl-L-cysteine N-palmitoylation / 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 ...N-terminal peptidyl-L-cysteine N-palmitoylation / 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 / Formation of lateral plate mesoderm / hindgut morphogenesis / O-acyltransferase activity / 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 / telencephalon regionalization / epithelial-mesenchymal cell signaling / laminin-1 binding / Ligand-receptor interactions / negative regulation of cholesterol efflux / salivary gland cavitation / spinal cord dorsal/ventral patterning / determination of left/right asymmetry in lateral mesoderm / negative regulation of mesenchymal cell apoptotic process / cell development / positive regulation of cerebellar granule cell precursor proliferation / negative regulation of T cell differentiation in thymus / palmitoyltransferase activity / 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 / prostate gland development / embryonic skeletal system development / limb bud formation / lung lobe morphogenesis / Activation of SMO / establishment of epithelial cell polarity / skeletal muscle fiber differentiation / thalamus development / embryonic digestive tract morphogenesis / somite development / patched binding / embryonic foregut morphogenesis / epithelial cell proliferation involved in salivary gland morphogenesis / hindbrain development / animal organ formation / ectoderm development / positive regulation of skeletal muscle tissue development / neuron fate commitment / stem cell development / negative regulation of dopaminergic neuron differentiation / mesenchymal cell proliferation involved in lung development / skeletal muscle cell proliferation / negative thymic T cell selection / lymphoid progenitor cell differentiation / positive regulation of immature T cell proliferation in thymus / dorsal/ventral neural tube patterning / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / smooth muscle tissue development / regulation of stem cell proliferation / oligodendrocyte development / male genitalia development / artery development / positive regulation of astrocyte differentiation / pattern specification process / self proteolysis / epithelial cell proliferation involved in prostate gland development / positive regulation of epithelial cell proliferation involved in prostate gland development / embryonic pattern specification / branching involved in salivary gland morphogenesis / Release of Hh-Np from the secreting cell / lung-associated mesenchyme development / Formation of axial mesoderm / regulation of proteolysis / dopaminergic neuron differentiation / intein-mediated protein splicing / positive thymic T cell selection / metanephros development / metanephric collecting duct development Similarity search - Function | |||||||||
Biological species | ![]() ![]() ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.2 Å | |||||||||
![]() | Long SB / Jiang Y | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT. Authors: Yiyang Jiang / Thomas L Benz / Stephen B Long / ![]() Abstract: Hedgehog proteins govern crucial developmental steps in animals and drive certain human cancers. Before they can function as signaling molecules, Hedgehog precursor proteins must undergo amino- ...Hedgehog proteins govern crucial developmental steps in animals and drive certain human cancers. Before they can function as signaling molecules, Hedgehog precursor proteins must undergo amino-terminal palmitoylation by Hedgehog acyltransferase (HHAT). We present cryo-electron microscopy structures of human HHAT in complex with its palmitoyl-coenzyme A substrate and of a product complex with a palmitoylated Hedgehog peptide at resolutions of 2.7 and 3.2 angstroms, respectively. The structures reveal how HHAT overcomes the challenges of bringing together substrates that have different physiochemical properties from opposite sides of the endoplasmic reticulum membrane within a membrane-embedded active site for catalysis. These principles are relevant to related enzymes that catalyze the acylation of Wnt and of the appetite-stimulating hormone ghrelin. The structural and mechanistic insights may advance the development of inhibitors for cancer. | |||||||||
History |
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Structure visualization
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 187.3 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 14.3 KB 14.3 KB | Display Display | ![]() |
Images | ![]() | 118.9 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Validation report
Summary document | ![]() | 433.8 KB | Display | ![]() |
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Full document | ![]() | 433.3 KB | Display | |
Data in XML | ![]() | 7.2 KB | Display | |
Data in CIF | ![]() | 8.1 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7mhzMC ![]() 7mhyC M: atomic model generated by this map C: citing same article ( |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | final map | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.532 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
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Sample components
-Entire : HHAT in complex with a palmitoylated Hedgehog peptide product and...
Entire | Name: HHAT in complex with a palmitoylated Hedgehog peptide product and a Fab antibody fragment |
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Components |
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-Supramolecule #1: HHAT in complex with a palmitoylated Hedgehog peptide product and...
Supramolecule | Name: HHAT in complex with a palmitoylated Hedgehog peptide product and a Fab antibody fragment type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4 |
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Source (natural) | Organism: ![]() |
-Macromolecule #1: Sonic hedgehog protein N-product peptide
Macromolecule | Name: Sonic hedgehog protein N-product peptide / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 750.848 Da |
Sequence | String: CGPGRGFG |
-Macromolecule #2: Protein-cysteine N-palmitoyltransferase HHAT
Macromolecule | Name: Protein-cysteine N-palmitoyltransferase HHAT / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO EC number: Transferases; Acyltransferases; Transferring groups other than aminoacyl groups |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 57.358742 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MLPRWELALY LLASLGFHFY SFYEVYKVSR EHEEELDQEF ELETDTLFGG LKKDATDFEW SFWMEWGKQW LVWLLLGHMV VSQMATLLA RKHRPWILML YGMWACWCVL GTPGVAMVLL HTTISFCVAQ FRSQLLTWLC SLLLLSTLRL QGVEEVKRRW Y KTENEYYL ...String: MLPRWELALY LLASLGFHFY SFYEVYKVSR EHEEELDQEF ELETDTLFGG LKKDATDFEW SFWMEWGKQW LVWLLLGHMV VSQMATLLA RKHRPWILML YGMWACWCVL GTPGVAMVLL HTTISFCVAQ FRSQLLTWLC SLLLLSTLRL QGVEEVKRRW Y KTENEYYL LQFTLTVRCL YYTSFSLELC WQQLPAASTS YSFPWMLAYV FYYPVLHNGP ILSFSEFIKQ MQQQEHDSLK AS LCVLALG LGRLLCWWWL AELMAHLMYM HAIYSSIPLL ETVSCWTLGG LALAQVLFFY VKYLVLFGVP ALLMRLDGLT PPA LPRCVS TMFSFTGMWR YFDVGLHNFL IRYVYIPVGG SQHGLLGTLF STAMTFAFVS YWHGGYDYLW CWAALNWLGV TVEN GVRRL VETPCIQDSL ARYFSPQARR RFHAALASCS TSMLILSNLV FLGGNEVGKT YWNRIFIQGW PWVTLSVLGF LYCYS HVGI AWAQTYATD |
-Macromolecule #3: 3H02 Fab heavy chain
Macromolecule | Name: 3H02 Fab heavy chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 51.307891 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MGWSCIILFL VATATGVHSQ IQLVQSGPEL KKPGETVKIS CKASGYTFTN YGMNWVRQAP GKGLKWMGWI NTYTGEPTYA DDFKGRFAF SLETSASTAY LQINNLKDED MATYFCARVW NYDYYFDYWG QGTTLTVSSA KTTPPSVYPL APGSAAQTNS M VTLGCLVK ...String: MGWSCIILFL VATATGVHSQ IQLVQSGPEL KKPGETVKIS CKASGYTFTN YGMNWVRQAP GKGLKWMGWI NTYTGEPTYA DDFKGRFAF SLETSASTAY LQINNLKDED MATYFCARVW NYDYYFDYWG QGTTLTVSSA KTTPPSVYPL APGSAAQTNS M VTLGCLVK GYFPEPVTVT WNSGSLSSGV HTFPAVLQSD LYTLSSSVTV PSSPRPSETV TCNVAHPASS TKVDKKIVPR DC GCKPCIC TVPEVSSVFI FPPKPKDVLT ITLTPKVTCV VVDISKDDPE VQFSWFVDDV EVHTAQTQPR EEQFNSTFRS VSE LPIMHQ DWLNGKEFKC RVNSAAFPAP IEKTISKTKG RPKAPQVYTI PPPKEQMAKD KVSLTCMITD FFPEDITVEW QWNG QPAEN YKNTQPIMNT NGSYFVYSKL NVQKSNWEAG NTFTCSVLHE GLHNHHTEKS LSHSPGK |
-Macromolecule #4: 3H02 Fab light chain
Macromolecule | Name: 3H02 Fab light chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 22.868863 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MKLPVRLLVL MFWIPASRSD VLMTQTPLSL PVSLGDQVSI SCRSSQSIVH SNGNTYLEWY LQKPGQSPKL LIYRVSNRFS GVPDRFSGS GSGTDFTLKI SRVEAEDLGV YYCFQGSHVP WTFGGGTKLE IKRADAAPTV SIFPPSSEQL TSGGASVVCF L NNFYPKDI ...String: MKLPVRLLVL MFWIPASRSD VLMTQTPLSL PVSLGDQVSI SCRSSQSIVH SNGNTYLEWY LQKPGQSPKL LIYRVSNRFS GVPDRFSGS GSGTDFTLKI SRVEAEDLGV YYCFQGSHVP WTFGGGTKLE IKRADAAPTV SIFPPSSEQL TSGGASVVCF L NNFYPKDI NVKWKIDGSE RQNGVLNSWT DQDSKDSTYS MSSTLTLTK |
-Macromolecule #5: PALMITIC ACID
Macromolecule | Name: PALMITIC ACID / type: ligand / ID: 5 / Number of copies: 1 / Formula: PLM |
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Molecular weight | Theoretical: 256.424 Da |
Chemical component information | ![]() ChemComp-PLM: |
-Macromolecule #6: PROTOPORPHYRIN IX CONTAINING FE
Macromolecule | Name: PROTOPORPHYRIN IX CONTAINING FE / type: ligand / ID: 6 / Number of copies: 1 / Formula: HEM |
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Molecular weight | Theoretical: 616.487 Da |
Chemical component information | ![]() ChemComp-HEM: |
-Macromolecule #7: Palmitoyl-CoA
Macromolecule | Name: Palmitoyl-CoA / type: ligand / ID: 7 / Number of copies: 3 / Formula: PKZ |
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Molecular weight | Theoretical: 1.005943 KDa |
Chemical component information | ![]() ChemComp-PKZ: |
-Macromolecule #8: Digitonin
Macromolecule | Name: Digitonin / type: ligand / ID: 8 / Number of copies: 10 / Formula: AJP |
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Molecular weight | Theoretical: 1.229312 KDa |
Chemical component information | ![]() ChemComp-AJP: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 43.5 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Final reconstruction | Resolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 142121 |
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Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final angle assignment | Type: MAXIMUM LIKELIHOOD |