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

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 a...

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Autores principales: Besprozvannaya, Marina, Dickson, Eamonn, Li, Hao, Ginburg, Kenneth S, Bers, Donald M, Auwerx, Johan, Nunnari, Jodi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823543/
https://www.ncbi.nlm.nih.gov/pubmed/29469807
http://dx.doi.org/10.7554/eLife.31019
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author Besprozvannaya, Marina
Dickson, Eamonn
Li, Hao
Ginburg, Kenneth S
Bers, Donald M
Auwerx, Johan
Nunnari, Jodi
author_facet Besprozvannaya, Marina
Dickson, Eamonn
Li, Hao
Ginburg, Kenneth S
Bers, Donald M
Auwerx, Johan
Nunnari, Jodi
author_sort Besprozvannaya, Marina
collection PubMed
description 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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spelling pubmed-58235432018-02-23 GRAM domain proteins specialize functionally distinct ER-PM contact sites in human cells Besprozvannaya, Marina Dickson, Eamonn Li, Hao Ginburg, Kenneth S Bers, Donald M Auwerx, Johan Nunnari, Jodi eLife Cell Biology 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. eLife Sciences Publications, Ltd 2018-02-22 /pmc/articles/PMC5823543/ /pubmed/29469807 http://dx.doi.org/10.7554/eLife.31019 Text en © 2018, Besprozvannaya et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Cell Biology
Besprozvannaya, Marina
Dickson, Eamonn
Li, Hao
Ginburg, Kenneth S
Bers, Donald M
Auwerx, Johan
Nunnari, Jodi
GRAM domain proteins specialize functionally distinct ER-PM contact sites in human cells
title GRAM domain proteins specialize functionally distinct ER-PM contact sites in human cells
title_full GRAM domain proteins specialize functionally distinct ER-PM contact sites in human cells
title_fullStr GRAM domain proteins specialize functionally distinct ER-PM contact sites in human cells
title_full_unstemmed GRAM domain proteins specialize functionally distinct ER-PM contact sites in human cells
title_short GRAM domain proteins specialize functionally distinct ER-PM contact sites in human cells
title_sort gram domain proteins specialize functionally distinct er-pm contact sites in human cells
topic Cell Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823543/
https://www.ncbi.nlm.nih.gov/pubmed/29469807
http://dx.doi.org/10.7554/eLife.31019
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