Architecture of the human PI4KIIIα lipid kinase complex

Plasma membrane (PM) phosphoinositides play essential roles in cell physiology, serving as both markers of membrane identity and signaling molecules central to the cell’s interaction with its environment. The first step in PM phosphoinositide synthesis is the conversion of phosphatidylinositol (PI)...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 114; no. 52; pp. 13720 - 13725
Main Authors Lees, Joshua A., Zhang, Yixiao, Oh, Michael S., Schauder, Curtis M., Yu, Xiaoling, Baskin, Jeremy M., Dobbs, Kerry, Notarangelo, Luigi D., De Camilli, Pietro, Walz, Thomas, Reinisch, Karin M.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 26.12.2017
Subjects
Biological Sciences
Complexity
Conversion
Electron microscopy
Homeostasis
Lipid kinase
Membranes
Molecules
Phosphatidylinositol
Phosphatidylinositol 3,4,5-triphosphate
Phosphoinositides
Proteins
Regulatory subunits
Signaling
Synthesis
lipid kinase
phosphoinositides
signaling
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Summary:Plasma membrane (PM) phosphoinositides play essential roles in cell physiology, serving as both markers of membrane identity and signaling molecules central to the cell’s interaction with its environment. The first step in PM phosphoinositide synthesis is the conversion of phosphatidylinositol (PI) to PI4P, the precursor of PI(4,5)P₂ and PI(3,4,5)P₃. This conversion is catalyzed by the PI4KIIIα complex, comprising a lipid kinase, PI4KIIIα, and two regulatory subunits, TTC7 and FAM126. We here report the structure of this complex at 3.6-Å resolution, determined by cryo-electron microscopy. The proteins form an obligate ∼700-kDa superassembly with a broad surface suitable for membrane interaction, toward which the kinase active sites are oriented. The structural complexity of the assembly highlights PI4P synthesis as a major regulatory junction in PM phosphoinositide homeostasis. Our studies provide a framework for further exploring the mechanisms underlying PM phosphoinositide regulation.
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2Present address: National Translational Science Center for Molecular Medicine, Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi’an 710032, China.
Author contributions: J.A.L., Y.Z., C.M.S., J.M.B., P.D.C., T.W., and K.M.R. designed research; J.A.L., Y.Z., M.S.O., C.M.S., X.Y., J.M.B., and K.D. performed research; J.A.L., Y.Z., M.S.O., J.M.B., K.D., L.D.N., and P.D.C. analyzed data; J.A.L., Y.Z., P.D.C., T.W., and K.M.R. wrote the paper; and K.D. and L.D.N. genetically characterized patient cell lines.
3Present address: Department of Chemistry and Chemical Biology, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853.
Contributed by Pietro De Camilli, November 10, 2017 (sent for review October 23, 2017; reviewed by Nikolaus Grigorieff and James H. Hurley)
1J.A.L. and Y.Z. contributed equally to this work.
Reviewers: N.G., Howard Hughes Medical Institute; and J.H.H., University of California, Berkeley.
ISSN:0027-8424
1091-6490
1091-6490
DOI:10.1073/pnas.1718471115