近日，美国纪念斯隆-凯特琳癌症中心Stephen B. Long及其研究组揭示HHAT介导Hedgehog酰化的结构基础。相关论文发表在2021年6月11日出版的《科学》杂志上。

研究人员表示，Hedgehog蛋白控制着动物的关键发育步骤，并导致某些人类癌症。在它们能够作为信号分子发挥作用之前，Hedgehog前体蛋白必须通过Hedgehog酰基转移酶（HHAT）进行氨基末端棕榈酰化。

研究人员分别以2.7和3.2埃的分辨率展示了人类HHAT与其棕榈酰辅酶A底物结合和带有棕榈酰化Hedgehog肽产物复合物的冷冻电镜结构。这些结构揭示了HHAT如何克服将内质网膜两侧具有不同理化特性的底物聚集在膜嵌入活性位点内进行催化。这些原理与催化Wnt和促食欲激素ghrelin酰化的相关酶有关。 这些结构和机制的见解可能会促进癌症抑制剂的开发。

附：英文原文

Title: Substrate and product complexes reveal mechanisms of Hedgehog acylation by HHAT

Author: Yiyang Jiang, Thomas L. Benz, Stephen B. Long

Issue&Volume: 2021/06/11

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.

DOI: 10.1126/science.abg4998

Source: https://science.sciencemag.org/content/372/6547/1215