Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT

doi:10.1126/science.abg4998

GSTDTAP > 气候变化

DOI	10.1126/science.abg4998
	Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT
	Yiyang Jiang; Thomas L. Benz; Stephen B. Long
	2021-06-11
发表期刊	Science
出版年	2021
英文摘要	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][1] 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. [1]: /lookup/doi/10.1126/science.abg4998
领域	气候变化 ; 资源环境
URL	查看原文
引用统计	被引频次：33[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/329917
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Yiyang Jiang,Thomas L. Benz,Stephen B. Long. Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT[J]. Science,2021.
APA	Yiyang Jiang,Thomas L. Benz,&Stephen B. Long.(2021).Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT.Science.
MLA	Yiyang Jiang,et al."Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT".Science (2021).