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TitleStructure of calcineurin bound to PI4KA reveals dual interface in both PI4KA and FAM126A.
Journal, issue, pagesStructure, Vol. 32, Issue 11, Page 1973-11983.e6, Year 2024
Publish dateNov 7, 2024
AuthorsAlexandria L Shaw / Sushant Suresh / Matthew A H Parson / Noah J Harris / Meredith L Jenkins / Calvin K Yip / John E Burke /
PubMed AbstractPhosphatidylinositol 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 ...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.
External linksStructure / PubMed:39216471
MethodsEM (single particle)
Resolution3.5 Å
Structure data

44382

9b9g

EMDB-44382, PDB-9b9g:
Structure of the PI4KA complex bound to Calcineurin
Method: EM (single particle) / Resolution: 3.5 Å

Chemicals

ChemComp-CA:
Unknown entry

Source
  • homo sapiens (human)
KeywordsSIGNALING PROTEIN / PI4KIIIa complex / PI4KA / TTC7B / FAM126A / CNA / CNB / Calcineurin

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