The lipid kinase phosphatidylinositol 4 kinase III α (PI4KIIIα/PI4KA) is a master regulator of the lipid composition and asymmetry of the plasma membrane. PI4KA exists primarily in a heterotrimeric complex with its regulatory proteins TTC7 and FAM126. Fundamental to PI4KA activity is its targeted recruitment to the plasma membrane by the lipidated proteins EFR3A and EFR3B. Here, we report a cryogenic electron microscopy structure of the C terminus of EFR3A bound to the PI4KA-TTC7B-FAM126A complex, with extensive validation using both hydrogen deuterium exchange mass spectrometry, and mutational analysis. The EFR3A C terminus undergoes a disorder-order transition upon binding to the PI4KA complex, with an unexpected direct interaction with both TTC7B and FAM126A. Complex disrupting mutations in TTC7B, FAM126A, and EFR3 decrease PI4KA recruitment to the plasma membrane. Multiple posttranslational modifications and disease linked mutations map to this site, providing insight into how PI4KA membrane recruitment can be regulated and disrupted in human disease.

中文翻译：

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EFR3 质膜募集 PI4KA 的分子基础


脂质激酶磷脂酰肌醇 4 激酶 III α （PI4KIIIα/PI4KA） 是脂质组成和质膜不对称性的主要调节因子。PI4KA 主要存在于异源三聚体复合物中，其调节蛋白 TTC7 和 FAM126 存在。PI4KA 活性的基础是其脂质化蛋白 EFR3A 和 EFR3B 靶向募集到质膜。在这里，我们报道了与 PI4KA-TTC7B-FAM126A 复合物结合的 EFR3A C 末端的低温电子显微镜结构，并使用氢氘交换质谱和突变分析进行了广泛验证。EFR3A C 末端在与 PI4KA 复合体结合后发生无序转变，与 TTC7B 和 FAM126A发生意外的直接相互作用。TTC7B、FAM126A 和 EFR3 的复杂破坏突变减少了 PI4KA 向质膜的募集。多个翻译后修饰和疾病相关突变映射到该位点，为人类疾病中如何调节和破坏 PI4KA 膜募集提供了见解。