PI(4,5)P(2)-dependent and Ca(2+)-regulated ER-PM interactions mediated by the extended synaptotagmins

Cell. 2013 Jun 20;153(7):1494-509. doi: 10.1016/j.cell.2013.05.026.


Most available information on endoplasmic reticulum (ER)-plasma membrane (PM) contacts in cells of higher eukaryotes concerns proteins implicated in the regulation of Ca(2+) entry. However, growing evidence suggests that such contacts play more general roles in cell physiology, pointing to the existence of additionally ubiquitously expressed ER-PM tethers. Here, we show that the three extended synaptotagmins (E-Syts) are ER proteins that participate in such tethering function via C2 domain-dependent interactions with the PM that require PI(4,5)P2 in the case of E-Syt2 and E-Syt3 and also elevation of cytosolic Ca(2+) in the case of E-Syt1. As they form heteromeric complexes, the E-Syts confer cytosolic Ca(2+) regulation to ER-PM contact formation. E-Syts-dependent contacts, however, are not required for store-operated Ca(2+) entry. Thus, the ER-PM tethering function of the E-Syts (tricalbins in yeast) mediates the formation of ER-PM contacts sites, which are functionally distinct from those mediated by STIM1 and Orai1.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Calcium / metabolism*
  • Cell Line, Tumor
  • Cell Membrane / chemistry
  • Cell Membrane / metabolism*
  • Cell Membrane / ultrastructure
  • Endoplasmic Reticulum / chemistry
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / ultrastructure
  • HeLa Cells
  • Humans
  • Molecular Sequence Data
  • Phosphatidylinositol 4,5-Diphosphate / metabolism*
  • Protein Structure, Tertiary
  • Sequence Alignment
  • Synaptotagmins / chemistry
  • Synaptotagmins / genetics
  • Synaptotagmins / metabolism*
  • Yeasts / cytology
  • Yeasts / metabolism


  • ESYT1 protein, human
  • ESYT2 protein, human
  • ESYT3 protein, human
  • Phosphatidylinositol 4,5-Diphosphate
  • Synaptotagmins
  • Calcium