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

ELife
Marina BesprozvannayaJodi Nunnari

Abstract

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.

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Datasets Mentioned

BETA
GSE9588
GSE60149

Methods Mentioned

BETA
biosensor
Fluorescence
transfection
confocal
confocal microscopy
FACS
genotyping

Software Mentioned

Slidebook
Studio Lite
GraphPad Prism
Image
Gene Set Enrichment Analysis ( GSEA )
MUSCLE
IGOR Pro Software
MEGA7
ImageJ
GSEA

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