title: PI(4,5)P(2)-dependent and Ca(2+)-regulated ER-PM interactions mediated by the extended synaptotagmins.
abstract: 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.
authors.affiliation: Department of Cell Biology, Program in Cellular Neuroscience, Neurodegeneration, and Repair, and Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06510, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Giordano
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Saheki
authors.forename: Olof
authors.initials: O
authors.lastname: Idevall-Hagren
authors.forename: Sara Francesca
authors.initials: SF
authors.lastname: Colombo
authors.forename: Michelle
authors.initials: M
authors.lastname: Pirruccello
authors.forename: Ira
authors.initials: I
authors.lastname: Milosevic
authors.forename: Elena O
authors.initials: EO
authors.lastname: Gracheva
authors.forename: Sviatoslav N
authors.initials: SN
authors.lastname: Bagriantsev
authors.forename: Nica
authors.initials: N
authors.lastname: Borgese
authors.forename: Pietro
authors.initials: P
authors.lastname: De Camilli
mesh_terms: D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D050857:Synaptotagmins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015003:Yeasts / Q000166:cytology / Q000378:metabolism
chemical_list: C583132:ESYT1 protein, human; C573315:ESYT2 protein, human; C571229:ESYT3 protein, human; D019269:Phosphatidylinositol 4,5-Diphosphate; D050857:Synaptotagmins; D002118:Calcium