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PreprintCited by 8Cellular transport and secretionSignaling Pathways in DiseaseProtein Kinase Regulation and GTPase Signaling

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

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

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Shaw, Alexandria L, Suresh, Sushant, Parson, Matthew AH, Harris, Noah J, Jenkins, Meredith L, Yip, Calvin K, Burke, John E·2024·Structure
DOI 10.1101/2024.04.09.588654

Preprint — published as 10.1016/j.str.2024.08.007 · Paper page

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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 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.

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Metadata

Authors
Shaw, A. L., Suresh, S., Parson, M. A., 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
openRxiv
Published
2024-04-09
Volume
32
Issue
11
Pages
1973-1983.e6
ISSN
0969-2126 (ISSN-L)
DOI
10.1101/2024.04.09.588654
OpenAlex
W4402041595
Cited by
8
References
1
Citations by year
2026: 3 · 2025: 4 · 2024: 1
FWCI
1.79
Type
journal article
Language
en
Open access
Locations
  • Structure (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Novartis
  • Canada Foundation for Innovation
  • Michael Smith Health Research BC (RGPIN-2018-03951, 2020-04241, 17686)
  • University of British Columbia
  • Canadian Institutes of Health Research (2020-04241, 195808_1, 168907, 168907_1, RGPIN-2018-03951)
  • Natural Sciences and Engineering Research Council of Canada (rgpin-2020-04241, rgpin-2018-03951, 2020-04241, RGPIN 2018)
  • British Columbia Knowledge Development Fund
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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