Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Science. 2021 Jun 11;372(6547):1215-1219. doi: 10.1126/science.abg4998.
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.
刺猬蛋白调控动物的关键发育步骤，并驱动某些人类癌症。在作为信号分子发挥功能之前，刺猬蛋白前体必须通过刺猬酰基转移酶（HHAT）进行氨基末端棕榈酰化。我们展示了人 HHAT 与棕榈酰辅酶 A 底物的复合物以及与棕榈酰化刺猬肽的产物复合物的冷冻电镜结构，分辨率分别为 2.7 和 3.2 埃。这些结构揭示了 HHAT 如何克服将具有不同理化性质的底物在膜嵌入活性位点内从内质网膜的相对侧聚集在一起以进行催化的挑战。这些原则与催化 Wnt 和食欲刺激激素 ghrelin 酰化的相关酶有关。结构和机制上的见解可能会促进癌症抑制剂的开发。
