Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong, China.
Nat Struct Mol Biol. 2021 Mar;28(3):249-257. doi: 10.1038/s41594-020-00553-7. Epub 2021 Feb 8.
Human serine palmitoyltransferase (SPT) complex catalyzes the initial and rate-limiting step in the de novo biosynthesis of all sphingolipids. ORMDLs regulate SPT function, with human ORMDL3 being related to asthma. Here we report three high-resolution cryo-EM structures: the human SPT complex, composed of SPTLC1, SPTLC2 and SPTssa; the SPT-ORMDL3 complex; and the SPT-ORMDL3 complex bound to two substrates, PLP-L-serine (PLS) and a non-reactive palmitoyl-CoA analogue. SPTLC1 and SPTLC2 form a dimer of heterodimers as the catalytic core. SPTssa participates in acyl-CoA coordination, thereby stimulating the SPT activity and regulating the substrate selectivity. ORMDL3 is located in the center of the complex, serving to stabilize the SPT assembly. Our structural and biochemical analyses provide a molecular basis for the assembly and substrate selectivity of the SPT and SPT-ORMDL3 complexes, and lay a foundation for mechanistic understanding of sphingolipid homeostasis and for related therapeutic drug development.
人丝氨酸棕榈酰转移酶（SPT）复合物催化所有神经鞘脂从头生物合成的初始和限速步骤。ORMDLs 调节 SPT 功能，人 ORMDL3 与哮喘有关。在这里，我们报告了三个高分辨率的冷冻电镜结构：由 SPTLC1、SPTLC2 和 SPTssa 组成的人 SPT 复合物；SPT-ORMDL3 复合物；以及与两种底物，PLP-L-丝氨酸（PLS）和非反应性棕榈酰辅酶 A 类似物结合的 SPT-ORMDL3 复合物。SPTLC1 和 SPTLC2 形成二聚体异二聚体作为催化核心。SPTssa 参与酰基辅酶 A 的配位，从而刺激 SPT 活性并调节底物选择性。ORMDL3 位于复合物的中心，用于稳定 SPT 组装。我们的结构和生化分析为 SPT 和 SPT-ORMDL3 复合物的组装和底物选择性提供了分子基础，并为理解神经鞘脂稳态的机制和相关治疗药物的开发奠定了基础。
