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GRAM 结构域蛋白在人类细胞中特化出具有不同功能的内质网-质膜接触位点。

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

机构信息

Department of Molecular and Cellular Biology, University of California, Davis, Davis, United States.

Department of Physiology and Membrane Biology, School of Medicine, University of California, Davis, Davis, United States.

出版信息

Elife. 2018 Feb 22;7:e31019. doi: 10.7554/eLife.31019.

DOI:10.7554/eLife.31019
PMID:29469807
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5823543/
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.

摘要

内质网 (ER) 膜接触位点 (MCSs) 是细胞中至关重要的调节枢纽，在信号转导、细胞器动态以及离子和脂质动态平衡中发挥作用。先前的工作表明，高度保守的酵母 Ltc/Lam 固醇转运蛋白定位于 ER MCSs 并在此发挥功能。我们对人类家族成员 GRAMD1a 和 GRAMD2a 的分析表明，它们是 ER-PM MCS 蛋白，标记质膜 (PM) 的不同区域，并在体内执行不同的功能。GRAMD2a（而非 GRAMD1a）以 PIP 脂质依赖性方式与 E-Syt2/3 接头共定位于 ER-PM 接触部位，并预先标记用于 STIM1 募集的 PI(4,5)P2 富集的 ER-PM MCS 亚集。缺乏 GRAMD2a 的细胞分析数据表明，它是 ER-PM MCS 的组织者，具有包括钙稳态在内的多种多功能性。因此，我们的数据表明，人类细胞中存在多个具有 GRAM 结构域蛋白功能特化的 ER-PM 结构域。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5875/5823543/2df6fa4a3e2a/elife-31019-fig8-figsupp1.jpg
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