在哺乳动物细胞中，两种磷脂酰丝氨酸 (PS) 合酶驱动 PS 合成。 Ptdss1 基因的功能获得性突变会导致 PS 产生增加，从而导致 Lenz-Majewski 综合征 (LMS)。最近，PSS1 的药理学抑制已被证明可以抑制肿瘤发生。在这里，我们报道了野生型人类 PSS1 (PSS1WT)、引起 LMS 的 Pro269Ser 突变体 (PSS1P269S) 以及 PSS1WT 与其抑制剂 DS55980254 的复合物的冷冻电镜结构。 PSS1 包含 10 个跨膜螺旋 (TM)，其中 TM 4-8 在管腔小叶中形成催化核心。这些结构揭示了 PSS1 的工作机制，类似于膜结合 O-酰基转移酶家族的假设机制。此外，我们发现 PS 和 DS55980254 都可以变构抑制 PSS1，并且 DS55980254 的抑制会激活 SREBP 途径，从而增强 LDL 受体的表达并增加细胞 LDL 摄取。这项工作揭示了哺乳动物 PS 合成的机制，并表明选择性 PSS1 抑制剂具有降低血液胆固醇水平的潜力。版权所有 © 2024 Elsevier Inc. 保留所有权利。

In mammalian cells, two phosphatidylserine (PS) synthases drive PS synthesis. Gain-of-function mutations in the Ptdss1 gene lead to heightened PS production, causing Lenz-Majewski syndrome (LMS). Recently, pharmacological inhibition of PSS1 has been shown to suppress tumorigenesis. Here, we report the cryo-EM structures of wild-type human PSS1 (PSS1WT), the LMS-causing Pro269Ser mutant (PSS1P269S), and PSS1WT in complex with its inhibitor DS55980254. PSS1 contains 10 transmembrane helices (TMs), with TMs 4-8 forming a catalytic core in the luminal leaflet. These structures revealed a working mechanism of PSS1 akin to the postulated mechanisms of the membrane-bound O-acyltransferase family. Additionally, we showed that both PS and DS55980254 can allosterically inhibit PSS1 and that inhibition by DS55980254 activates the SREBP pathways, thus enhancing the expression of LDL receptors and increasing cellular LDL uptake. This work uncovers a mechanism of mammalian PS synthesis and suggests that selective PSS1 inhibitors have the potential to lower blood cholesterol levels.Copyright © 2024 Elsevier Inc. All rights reserved.