9b9g

Structure of the PI4KA complex bound to Calcineurin

spinqualitylabelsall models 9b9g, resolution 3.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9b9g is a 10 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.5Å Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease PI4KA_HUMAN Combined immunodeficiency-enteropathy spectrum;Autosomal recessive spastic paraplegia type 84;Bilateral perisylvian polymicrogyria. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. Function PI4KA_HUMAN Acts on phosphatidylinositol (PtdIns) in the first committed step in the production of the second messenger inositol-1,4,5,-trisphosphate. Publication Abstract from PubMed 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 CNAbeta1 isoform of the phosphatase calcineurin. We previously identified that CNAbeta1 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. Structure of calcineurin bound to PI4KA reveals dual interface in both PI4KA and FAM126A.,Shaw AL, Suresh S, Parson MAH, Harris NJ, Jenkins ML, Yip CK, Burke JE Structure. 2024 Aug 22:S0969-2126(24)00324-1. doi: 10.1016/j.str.2024.08.007. PMID:39216471 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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