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GRAM domain proteins specialize functionally distinct ER-PM contact sites in human cells.

eLife | 2018

Endoplasmic reticulum (ER) membrane contact sites (MCSs) are crucial regulatory hubs in cells, playing roles in signaling, organelle dynamics, and ion and lipid homeostasis. Previous work demonstrated that the highly conserved yeast Ltc/Lam sterol transporters localize and function at ER MCSs. Our analysis of the human family members, GRAMD1a and GRAMD2a, demonstrates that they are ER-PM MCS proteins, which mark separate regions of the plasma membrane (PM) and perform distinct functions in vivo. GRAMD2a, but not GRAMD1a, co-localizes with the E-Syt2/3 tethers at ER-PM contacts in a PIP lipid-dependent manner and pre-marks the subset of PI(4,5)P2-enriched ER-PM MCSs utilized for STIM1 recruitment. Data from an analysis of cells lacking GRAMD2a suggest that it is an organizer of ER-PM MCSs with pleiotropic functions including calcium homeostasis. Thus, our data demonstrate the existence of multiple ER-PM domains in human cells that are functionally specialized by GRAM-domain containing proteins.

Pubmed ID: 29469807 RIS Download

Associated grants

  • Agency: NCI NIH HHS, United States
    Id: P30 CA093373
  • Agency: NIH HHS, United States
    Id: S10 OD018223
  • Agency: NIA NIH HHS, United States
    Id: R01 AG043930
  • Agency: NIGMS NIH HHS, United States
    Id: F32GM117689
  • Agency: NHLBI NIH HHS, United States
    Id: R01 HL030077
  • Agency: NIAAA NIH HHS, United States
    Id: R01 AA016957
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM097432
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM062942
  • Agency: NIGMS NIH HHS, United States
    Id: R37 GM097432
  • Agency: NIGMS NIH HHS, United States
    Id: R01GM062942
  • Agency: NIGMS NIH HHS, United States
    Id: R01GM097432
  • Agency: NIGMS NIH HHS, United States
    Id: R01 GM106019
  • Agency: NIGMS NIH HHS, United States
    Id: F32 GM117689
  • Agency: NHLBI NIH HHS, United States
    Id: R37 HL030077

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