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

• DOI: 10.1016/j.str.2024.08.007
• Publication Date: 2024-08-30T17:02:03Z
• Authors: Alexandria L. Shaw; Sushant Suresh; Matthew A.H. Parson; Noah J. Harris; Meredith L. Jenkins; Calvin K. Yip; John E. Burke
• Keywords: 0301 basic medicine; 03 medical and health sciences

AbstractPhosphatidylinositol 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 CNAβ1 isoform of the phosphatase Calcineurin. We previously identified that CNAβ1 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 PI4KA’s 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.