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- PDB-7mhz: Human Hedgehog acyltransferase (HHAT) in complex with a palmitoyl... -

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Basic information

Entry
Database: PDB / ID: 7mhz
TitleHuman Hedgehog acyltransferase (HHAT) in complex with a palmitoylated Hedgehog peptide product and a Fab antibody fragment
Components
  • 3H02 Fab heavy chain
  • 3H02 Fab light chain
  • Protein-cysteine N-palmitoyltransferase HHAT
  • Sonic hedgehog protein N-product peptide
KeywordsTRANSFERASE/IMMUNE SYSTEM / MBOAT / GOAT / porcupine / acyl transferase / membrane protein / membrane enzyme / ER / palmitoyl-CoA / TRANSFERASE-IMMUNE SYSTEM complex
Function / homology
Function and homology information


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 / regulation of odontogenesis / positive regulation of mesenchymal cell proliferation involved in ureter development / cerebellar granule cell precursor proliferation / Formation of lateral plate mesoderm ...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 / regulation of odontogenesis / positive regulation of mesenchymal cell proliferation involved in ureter development / cerebellar granule cell precursor proliferation / Formation of lateral plate mesoderm / epithelial-mesenchymal cell signaling / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / polarity specification of anterior/posterior axis / ventral midline development / morphogen activity / metanephric mesenchymal cell proliferation involved in metanephros development / cholesterol-protein transferase activity / HHAT G278V doesn't palmitoylate Hh-Np / protein-cysteine S-palmitoyltransferase activity / negative thymic T cell selection / Ligand-receptor interactions / laminin-1 binding / positive regulation of T cell differentiation in thymus / stem cell development / determination of left/right asymmetry in lateral mesoderm / negative regulation of cholesterol efflux / lymphoid progenitor cell differentiation / palmitoyltransferase activity / metanephric collecting duct development / cell development / somite development / prostate gland development / male genitalia development / neuroblast proliferation / hindbrain development / metanephros development / embryonic limb morphogenesis / neuron fate commitment / Developmental Lineage of Multipotent Pancreatic Progenitor Cells / patched binding / smooth muscle tissue development / positive regulation of immature T cell proliferation in thymus / pattern specification process / negative regulation of dopaminergic neuron differentiation / Activation of SMO / dopaminergic neuron differentiation / embryonic pattern specification / Release of Hh-Np from the secreting cell / androgen metabolic process / oligodendrocyte differentiation / cell fate specification / positive thymic T cell selection / glycosaminoglycan binding / positive regulation of alpha-beta T cell differentiation / dorsal/ventral pattern formation / Formation of axial mesoderm / neural crest cell migration / intein-mediated protein splicing / branching involved in blood vessel morphogenesis / smoothened signaling pathway / regulation of protein localization to nucleus / branching involved in ureteric bud morphogenesis / branching morphogenesis of an epithelial tube / embryonic digit morphogenesis / Class B/2 (Secretin family receptors) / forebrain development / positive regulation of cell division / midbrain development / heart looping / thymus development / positive regulation of smoothened signaling pathway / protein autoprocessing / lung development / vasculogenesis / negative regulation of cell differentiation / regulation of proteolysis / T cell differentiation in thymus / Transferases; Acyltransferases; Transferring groups other than aminoacyl groups / axon guidance / apoptotic signaling pathway / negative regulation of cell migration / central nervous system development / protein maturation / Hh mutants are degraded by ERAD / Hedgehog ligand biogenesis / Hedgehog 'on' state / heart development / regulation of gene expression / regulation of cell population proliferation / cell-cell signaling / endopeptidase activity / extracellular matrix / Hydrolases; Acting on ester bonds / membrane raft / endoplasmic reticulum lumen / negative regulation of gene expression / Golgi membrane / calcium ion binding / positive regulation of cell population proliferation / negative regulation of apoptotic process
Similarity search - Function
: / Hedgehog, N-terminal signalling domain / Hedgehog protein / Hedgehog protein, Hint domain / : / Hint module / Hedgehog amino-terminal signalling domain / Membrane bound O-acyl transferase, MBOAT / MBOAT, membrane-bound O-acyltransferase family / Hedgehog signalling/DD-peptidase zinc-binding domain superfamily ...: / Hedgehog, N-terminal signalling domain / Hedgehog protein / Hedgehog protein, Hint domain / : / Hint module / Hedgehog amino-terminal signalling domain / Membrane bound O-acyl transferase, MBOAT / MBOAT, membrane-bound O-acyltransferase family / Hedgehog signalling/DD-peptidase zinc-binding domain superfamily / 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
PROTOPORPHYRIN IX CONTAINING FE / Palmitoyl-CoA / PALMITIC ACID / Sonic hedgehog protein / Protein-cysteine N-palmitoyltransferase HHAT
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsLong, S.B. / Jiang, Y.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM131921 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)P30CA008748 United States
CitationJournal: Science / Year: 2021
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
DepositionApr 16, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 16, 2021Provider: repository / Type: Initial release
Revision 1.0Jun 16, 2021Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.1Jul 14, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 2.0Aug 25, 2021Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references
Category: atom_site / database_2 ...atom_site / database_2 / database_PDB_caveat / pdbx_unobs_or_zero_occ_atoms / pdbx_validate_chiral
Item: _atom_site.Cartn_x / _atom_site.Cartn_y ..._atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_atom_id / _atom_site.label_atom_id / _atom_site.type_symbol / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_unobs_or_zero_occ_atoms.auth_atom_id / _pdbx_unobs_or_zero_occ_atoms.label_atom_id
Revision 2.1Oct 9, 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 2.2Aug 12, 2026Group: Data collection / Derived calculations
Category: em_admin / pdbx_nonpoly_atom_coordination ...em_admin / pdbx_nonpoly_atom_coordination / pdbx_nonpoly_atom_coordination_sphere / pdbx_nonpoly_atom_coordination_sphere_order
Item: _em_admin.last_update / Description: Metalloprotein remediation / Provider: repository / Type: Remediation
Revision 1.1Aug 12, 2026Data content type: EM metadata / Data content type: EM metadata / Group: Experimental summary / Data content type: EM metadata / Category: em_admin / Data content type: EM metadata / Item: _em_admin.last_update

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Structure visualization

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Assembly

Deposited unit
B: Sonic hedgehog protein N-product peptide
A: Protein-cysteine N-palmitoyltransferase HHAT
O: 3H02 Fab heavy chain
P: 3H02 Fab light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)148,47019
Polymers132,2864
Non-polymers16,18415
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area6370 Å2
ΔGint-46 kcal/mol
Surface area32150 Å2

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Components

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Antibody , 2 types, 2 molecules OP

#3: Antibody 3H02 Fab heavy chain


Mass: 51307.891 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse)
#4: Antibody 3H02 Fab light chain


Mass: 22868.863 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Mus musculus (house mouse)

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Protein/peptide / Protein , 2 types, 2 molecules BA

#1: Protein/peptide Sonic hedgehog protein N-product peptide / ShhN / Shh N-terminal processed signaling domains / ShhNp


Mass: 750.848 Da / Num. of mol.: 1 / Fragment: UNP residues 24-31 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15465
#2: Protein Protein-cysteine N-palmitoyltransferase HHAT / Hedgehog acyltransferase / Melanoma antigen recognized by T-cells 2 / MART-2 / Skinny hedgehog protein 1


Mass: 57358.742 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HHAT, MART2, SKI1 / Production host: Homo sapiens (human)
References: UniProt: Q5VTY9, Transferases; Acyltransferases; Transferring groups other than aminoacyl groups

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Non-polymers , 4 types, 15 molecules

#5: Chemical ChemComp-PLM / PALMITIC ACID


Mass: 256.424 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H32O2 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME


Mass: 616.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H32FeN4O4 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-PKZ / Palmitoyl-CoA


Mass: 1005.943 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C37H66N7O17P3S / Feature type: SUBJECT OF INVESTIGATION
#8: Chemical
ChemComp-AJP / Digitonin


Mass: 1229.312 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C56H92O29 / Comment: detergent*YM

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Details

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

ComponentName: HHAT in complex with a palmitoylated Hedgehog peptide product and a Fab antibody fragment
Type: COMPLEX / Entity ID: #1-#4 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Mus musculus (house mouse)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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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: 43.5 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

Software
NameVersionClassification
phenix.real_space_refine1.18.2_3874+SVNrefinement
PHENIX1.18.2_3874+SVNrefinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 142121 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 112.57 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00366436
ELECTRON MICROSCOPYf_angle_d0.66858909
ELECTRON MICROSCOPYf_chiral_restr0.04871019
ELECTRON MICROSCOPYf_plane_restr0.0039993
ELECTRON MICROSCOPYf_dihedral_angle_d18.91422315

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