Structure of calcineurin bound to PI4KA reveals dual interface in both PI4KA and FAM126A

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Structure Pub Date : 2024-08-30 DOI:10.1016/j.str.2024.08.007

Alexandria L. Shaw, Sushant Suresh, Matthew A.H. Parson, Noah J. Harris, Meredith L. Jenkins, Calvin K. Yip, John E. Burke

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Abstract

Phosphatidylinositol 4-kinase alpha (PI4KA) maintains the phosphatidylinositol 4-phosphate (PI4P) and phosphatidylserine pools of the plasma membrane. A key regulator of PI4KA is its association into a complex with TTC7 and FAM126 proteins. This complex can be regulated by the CNAβ1 isoform of the phosphatase calcineurin. We previously identified that CNAβ1 directly binds to FAM126A. Here, we report a cryoelectron microscopic (cryo-EM) structure of a truncated PI4KA complex bound to calcineurin, revealing a unique direct interaction between PI4KA and calcineurin. Hydrogen deuterium exchange mass spectrometry (HDX-MS) and computational analysis show that calcineurin forms a complex with an evolutionarily conserved IKISVT sequence in PI4KA’s horn domain. We also characterized conserved LTLT and PSISIT calcineurin binding sequences in the C terminus of FAM126A. These dual sites in PI4KA and FAM126A are both in close proximity to phosphorylation sites in the PI4KA complex, suggesting key roles of calcineurin-regulated phosphosites in PI4KA regulation. This work reveals novel insight into how calcineurin can regulate PI4KA activity.

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与 PI4KA 结合的钙神经蛋白的结构揭示了 PI4KA 和 FAM126A 的双重界面

磷脂酰肌醇 4-激酶α（PI4KA）维持着质膜的磷脂酰肌醇 4-磷酸（PI4P）和磷脂酰丝氨酸池。PI4KA 的一个关键调节因子是它与 TTC7 和 FAM126 蛋白形成的复合物。该复合物可由磷酸酶钙调磷酸酶的 CNAβ1 异构体调节。我们之前发现 CNAβ1 可直接与 FAM126A 结合。在这里，我们报告了与钙调素结合的截短 PI4KA 复合物的冷冻电镜（cryo-EM）结构，揭示了 PI4KA 与钙调素之间独特的直接相互作用。氢氘交换质谱（HDX-MS）和计算分析表明，钙调素与 PI4KA 角域中进化保守的 IKISVT 序列形成复合物。我们还鉴定了 FAM126A C 末端保守的 LTLT 和 PSISIT 钙调素结合序列。PI4KA 和 FAM126A 中的这些双重位点都非常接近 PI4KA 复合物中的磷酸化位点，这表明钙神经蛋白调控的磷酸化位点在 PI4KA 的调控中起着关键作用。这项工作揭示了钙调素如何调控 PI4KA 活性的新见解。

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来源期刊

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.