Architecture of the human PI4KIIIα lipid kinase complex

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Phosphatidylinositol 4-Kinase / chemistry*
  • 1-Phosphatidylinositol 4-Kinase / metabolism
  • Cryoelectron Microscopy
  • Intracellular Signaling Peptides and Proteins / chemistry*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Membrane Proteins / chemistry*
  • Membrane Proteins / metabolism
  • Models, Molecular*
  • Multiprotein Complexes / chemistry*
  • Multiprotein Complexes / metabolism
  • Phosphatidylinositol 4,5-Diphosphate / chemistry*
  • Phosphatidylinositol 4,5-Diphosphate / metabolism
  • Phosphatidylinositol Phosphates / chemistry*
  • Phosphatidylinositol Phosphates / metabolism
  • Proteins / chemistry*
  • Proteins / metabolism

Substances

  • FAM126A protein, human
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Multiprotein Complexes
  • Phosphatidylinositol 4,5-Diphosphate
  • Phosphatidylinositol Phosphates
  • Proteins
  • TTC7A protein, human
  • phosphatidylinositol 3,4,5-triphosphate
  • 1-Phosphatidylinositol 4-Kinase
  • PI4KIIIalpha protein, human