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-Structure paper
タイトル | Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT. |
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ジャーナル・号・ページ | Science, Vol. 372, Issue 6547, Page 1215-1219, Year 2021 |
掲載日 | 2021年6月11日 |
著者 | Yiyang Jiang / Thomas L Benz / Stephen B Long / |
PubMed 要旨 | 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. |
リンク | Science / PubMed:34112694 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.7 - 3.2 Å |
構造データ | EMDB-23836, PDB-7mhy: EMDB-23837, PDB-7mhz: |
化合物 | ChemComp-HEM: ChemComp-PKZ: ChemComp-AJP: ChemComp-HOH: ChemComp-PLM: |
由来 |
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キーワード | TRANSFERASE/IMMUNE SYSTEM / MBOAT / GOAT / porcupine / acyl transferase / membrane protein / membrane enzyme / ER / palmitoyl-CoA / TRANSFERASE-IMMUNE SYSTEM complex |