Functional anatomy of phospholipid binding and regulation of phosphoinositide homeostasis by proteins of the sec14 superfamily

Mol Cell. 2008 Feb 1;29(2):191-206. doi: 10.1016/j.molcel.2007.11.026.

Abstract

Sec14, the major yeast phosphatidylinositol (PtdIns)/phosphatidylcholine (PtdCho) transfer protein, regulates essential interfaces between lipid metabolism and membrane trafficking from the trans-Golgi network (TGN). How Sec14 does so remains unclear. We report that Sec14 binds PtdIns and PtdCho at distinct (but overlapping) sites, and both PtdIns- and PtdCho-binding activities are essential Sec14 activities. We further show both activities must reside within the same molecule to reconstitute a functional Sec14 and for effective Sec14-mediated regulation of phosphoinositide homeostasis in vivo. This regulation is uncoupled from PtdIns-transfer activity and argues for an interfacial presentation mode for Sec14-mediated potentiation of PtdIns kinases. Such a regulatory role for Sec14 is a primary counter to action of the Kes1 sterol-binding protein that antagonizes PtdIns 4-OH kinase activity in vivo. Collectively, these findings outline functional mechanisms for the Sec14 superfamily and reveal additional layers of complexity for regulating phosphoinositide homeostasis in eukaryotes.

Publication types

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

MeSH terms

  • 1-Phosphatidylinositol 4-Kinase / chemistry
  • 1-Phosphatidylinositol 4-Kinase / genetics
  • 1-Phosphatidylinositol 4-Kinase / metabolism
  • Biological Transport / physiology
  • Cell Membrane / chemistry
  • Cell Membrane / genetics
  • Cell Membrane / metabolism*
  • Golgi Apparatus / chemistry
  • Golgi Apparatus / genetics
  • Golgi Apparatus / metabolism
  • Homeostasis / physiology*
  • Lipid Metabolism / physiology*
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism
  • Phosphatidylcholines / chemistry
  • Phosphatidylcholines / genetics
  • Phosphatidylcholines / metabolism
  • Phosphatidylinositols / chemistry
  • Phosphatidylinositols / genetics
  • Phosphatidylinositols / metabolism*
  • Phospholipid Transfer Proteins / chemistry
  • Phospholipid Transfer Proteins / genetics
  • Phospholipid Transfer Proteins / metabolism*
  • Protein Structure, Tertiary
  • Receptors, Steroid
  • Saccharomyces cerevisiae / chemistry
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*

Substances

  • KES1 protein, S cerevisiae
  • Membrane Proteins
  • Phosphatidylcholines
  • Phosphatidylinositols
  • Phospholipid Transfer Proteins
  • Receptors, Steroid
  • SEC14 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • 1-Phosphatidylinositol 4-Kinase

Associated data

  • PDB/3B74
  • PDB/3B7N
  • PDB/3B7Q
  • PDB/3B7Z