Structural insights into the assembly and substrate selectivity of human SPT-ORMDL3 complex
Structural insights into the assembly and substrate selectivity of human SPT-ORMDL3 complex
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DOI：
10.1038/s41594-020-00553-7
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发表时间：
2021-02-08
影响因子：
16.8
通讯作者：
Gong, Xin
中科院分区：
文献类型：
--
作者：
Li, Sisi;Xie, Tian;Gong, Xin
人丝氨酸棕榈酰转移酶（SPT）复合物催化所有鞘脂从头生物合成的起始和限速步骤。ORMDL调节SPT功能，其中人ORMDL 3与哮喘相关。在这里，我们报告了三个高分辨率的冷冻EM结构：人SPT复合物，由SPTLC 1，SPTLC 2和SPTsa组成; SPT-ORMDL 3复合物;和SPT-ORMDL 3复合物结合到两个底物，PLP-l-丝氨酸（PLS）和非反应性棕榈酰辅酶A类似物。SPTLC 1和SPTLC 2形成异二聚体的二聚体作为催化核心。SPTssa参与酰基-CoA配位，从而刺激SPT活性并调节底物选择性。ORMDL 3位于复合体的中心，用于稳定SPT组装。我们的结构和生物化学分析为SPT和SPT-ORMDL 3复合物的组装和底物选择性提供了分子基础，并为了解鞘脂稳态的机制和相关治疗药物的开发奠定了基础。丝氨酸棕榈酰转移酶复合物介导鞘脂生物合成的关键反应的Cryo-EM结构阐明了其多聚体组装、调节和底物选择性的原理
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.Cryo-EM structures of serine palmitoyltransferase complexes mediating a key reaction of sphingolipid biosynthesis elucidate principles of its multimeric assembly, regulation and substrate selectivity