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TitleSubstrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT.
Journal, issue, pagesScience, Vol. 372, Issue 6547, Page 1215-1219, Year 2021
Publish dateJun 11, 2021
AuthorsYiyang Jiang / Thomas L Benz / Stephen B Long /
PubMed AbstractHedgehog 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.
External linksScience / PubMed:34112694 / PubMed Central
MethodsEM (single particle)
Resolution2.7 - 3.2 Å
Structure data

EMDB-23836, PDB-7mhy:
Human Hedgehog acyltransferase (HHAT) in complex with palmitoyl-CoA and two Fab antibody fragments
Method: EM (single particle) / Resolution: 2.7 Å

EMDB-23837, PDB-7mhz:
Human Hedgehog acyltransferase (HHAT) in complex with a palmitoylated Hedgehog peptide product and a Fab antibody fragment
Method: EM (single particle) / Resolution: 3.2 Å

Chemicals

ChemComp-HEM:
PROTOPORPHYRIN IX CONTAINING FE

ChemComp-PKZ:
Palmitoyl-CoA

ChemComp-AJP:
Digitonin / detergent*YM

ChemComp-HOH:
WATER

ChemComp-PLM:
PALMITIC ACID

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsTRANSFERASE/IMMUNE SYSTEM / MBOAT / GOAT / porcupine / acyl transferase / membrane protein / membrane enzyme / ER / palmitoyl-CoA / TRANSFERASE-IMMUNE SYSTEM complex

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