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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-02-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/31019 |
| _version_ | 1811236879313403904 |
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| author | Marina Besprozvannaya Eamonn Dickson Hao Li Kenneth S Ginburg Donald M Bers Johan Auwerx Jodi Nunnari |
| author_facet | Marina Besprozvannaya Eamonn Dickson Hao Li Kenneth S Ginburg Donald M Bers Johan Auwerx Jodi Nunnari |
| author_sort | Marina Besprozvannaya |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-12T12:15:43Z |
| format | Article |
| id | doaj.art-60c66a29d1814f5aa383d809ab92c5be |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:15:43Z |
| publishDate | 2018-02-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-60c66a29d1814f5aa383d809ab92c5be2022-12-22T03:33:26ZengeLife Sciences Publications LtdeLife2050-084X2018-02-01710.7554/eLife.31019GRAM domain proteins specialize functionally distinct ER-PM contact sites in human cellsMarina Besprozvannaya0https://orcid.org/0000-0001-5856-4130Eamonn Dickson1Hao Li2https://orcid.org/0000-0001-5677-3377Kenneth S Ginburg3Donald M Bers4Johan Auwerx5Jodi Nunnari6https://orcid.org/0000-0002-2249-8730Department of Molecular and Cellular Biology, University of California, Davis, Davis, United StatesDepartment of Physiology and Membrane Biology, School of Medicine, University of California, Davis, Davis, United StatesLaboratory of Integrative and Systems Physiology, EPFL, Lausanne, SwitzerlandDepartment of Pharmacology, University of California, Davis, Davis, United StatesDepartment of Pharmacology, University of California, Davis, Davis, United StatesLaboratory of Integrative and Systems Physiology, EPFL, Lausanne, SwitzerlandDepartment of Molecular and Cellular Biology, University of California, Davis, Davis, United StatesEndoplasmic 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.https://elifesciences.org/articles/31019membrane contact siteER-PM contact sitescortical ERGRAMD proteinsstore operated calcium entryPIP lipids |
| spellingShingle | Marina Besprozvannaya Eamonn Dickson Hao Li Kenneth S Ginburg Donald M Bers Johan Auwerx Jodi Nunnari GRAM domain proteins specialize functionally distinct ER-PM contact sites in human cells eLife membrane contact site ER-PM contact sites cortical ER GRAMD proteins store operated calcium entry PIP lipids |
| 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 | membrane contact site ER-PM contact sites cortical ER GRAMD proteins store operated calcium entry PIP lipids |
| url | https://elifesciences.org/articles/31019 |
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