Structure of calcineurin bound to PI4KA reveals dual interface in both PI4KA and FAM126A
Open accessPublished version of a preprint
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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Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Accurate structure prediction of biomolecular interactions with AlphaFold 3
Abramson, J., Adler, J., Dunger, J., Evans, R., Green, T., Pritzel, A., Ronneberger, O., Willmore, L., Ballard, A. J., Bambrick, J., et al. (2024) · Nature · doi:10.1038/s41586-024-07487-w · Cited by 15,861 · see citing works
Structural Basis for Regulation of Phosphoinositide Kinases and Their Involvement in Human Disease
Burke, J. E. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.08.005 · Cited by 276 · see citing works
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- Authors
- Shaw, A. L., Suresh, S., Parson, M. A. H., Harris, N. J., Jenkins, M. L., Yip, C. K., & Burke, J. E.
- Affiliations
- University of British Columbia (CA)
- University of Victoria (CA)
- Corresponding author
- Burke, John E.
- ORCID
- Venue
- Structure
- Publisher
- Elsevier BV
- Published
- 2024-11
- Volume
- 32
- Issue
- 11
- Pages
- 1973-1983.e6
- ISSN
- 0969-2126 (ISSN-L)
- OpenAlex
- W4402041595
- Cited by
- 8
- References
- 3
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 1
- FWCI
- 1.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 371 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Structure (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Natural Sciences and Engineering Research Council of Canada (RGPIN-2018-03951)
- MSFHR (17686)
- Novartis
- British Columbia Knowledge Development Fund
- Canadian Institutes of Health Research (PJT-168907, PJT-195808)
- Canada Foundation for Innovation
- University of British Columbia
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- calcineurin, PI4KA, phosphatidylinositol 4-phosphate, phosphatidylserine, protein-protein interaction, phosphatase regulation, phosphorylation sites, phospholipid metabolism
- MeSH terms
- Hydrogen Deuterium Exchange-Mass Spectrometry, Amino Acid Sequence, Binding Sites, Humans, Models, Molecular, Phosphorylation, Protein Binding, Calcineurin, Cryoelectron Microscopy
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