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bioRxiv · 10.1101/2024.04.09.588654

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

Shaw, A. L.·Suresh, S.·Parson, M. A.·Harris, N. J.·Jenkins, M. L.·Yip, C. K.·Burke, J. E.
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Abstract

Phosphatidylinositol 4-kinase alpha (PI4KA) maintains the 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 CNA{beta}1 isoform of the phosphatase Calcineurin. We previously identified that CNA{beta}1 directly binds to FAM126A. Here, we report a cryo-EM structure of a truncated PI4KA complex bound to Calcineurin, revealing a direct Calcineurin interaction with PI4KA. Additional HDX-MS and computational analysis show that Calcineurin forms a complex with an evolutionarily conserved IKISVT sequence in PI4KAs horn domain. We also characterised conserved LTLT and PSISIT Calcineurin binding sequences in the C-terminus of FAM126A. These sites are 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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Shaw, A. L., Suresh, S., Parson, M. A., Harris, N. J., Jenkins, M. L., Yip, C. K., Burke, J. E.. 2024-04-09. Structure of Calcineurin bound to PI4KA reveals dual interface in both PI4KA and FAM126A. https://doi.org/10.1101/2024.04.09.588654

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