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Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT

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Science  11 Jun 2021:
Vol. 372, Issue 6547, pp. 1215-1219
DOI: 10.1126/science.abg4998

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How Hedgehog gets its lipid tail

Phospholipid membranes serve as barriers between different cellular environments but are also crucial platforms for biosynthesis, signaling, and transport. In animals, the developmental signaling protein Hedgehog must be modified with an acyl group by the membrane-embedded enzyme Hedgehog acyltransferase (HHAT) to be recognized by its receptor. Using cryo–electron microscopy, Jiang et al. determined structures of HHAT bound to palmitoyl–coenzyme A or a palmitoylated peptide product. Two cavities connect at the active site, enabling acylation of Hedgehog in the lumen of the endoplasmic reticulum by lipid substrates from the cytosolic face of the membrane.

Science, abg4998, this issue p. 1215

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-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.

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