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Proc Natl Acad Sci U S A. 2017 Dec 26;114(52):13720-13725. doi: 10.1073/pnas.1718471115. Epub 2017 Dec 11.

Architecture of the human PI4KIIIα lipid kinase complex.

Author information

1
Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520.
2
Laboratory of Molecular Electron Microscopy, The Rockefeller University, New York, NY 10065.
3
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510.
4
Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT 06510.
5
Department of Cell Biology, Harvard Medical School, Boston, MA 02115.
6
Immune Deficiency Genetics Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
7
Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520; Pietro.decamilli@yale.edu twalz@mail.rockefeller.edu Karin.Reinisch@yale.edu.
8
Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06510.
9
Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT 06510.
10
Laboratory of Molecular Electron Microscopy, The Rockefeller University, New York, NY 10065; Pietro.decamilli@yale.edu twalz@mail.rockefeller.edu Karin.Reinisch@yale.edu.

Abstract

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.

KEYWORDS:

lipid kinase; phosphoinositides; signaling

PMID:
29229838
PMCID:
PMC5748228
DOI:
10.1073/pnas.1718471115
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

The authors declare no conflict of interest.

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