期刊
EMBO JOURNAL
卷 40, 期 6, 页码 -出版社
WILEY
DOI: 10.15252/embj.2020106524
关键词
cholesterol; GRAM domain; lipid sensor; membrane contact sites; plasma membrane
资金
- Singapore Ministry of Education Academic Research Fund Tier 2 [MOE2017-T22-001]
- Nanyang Assistant Professorship (NAP)
- Lee Kong Chian School of Medicine startup grant (LKCMedicine-SUG)
- Japan Society for Promotion of Science
The GRAM domain of GRAMD1b plays a crucial role in detecting cholesterol and anionic lipids, with mutations potentially leading to intellectual disabilities in humans. Cell utilize the GRAM domain to regulate the rate of cholesterol transport and membrane tethering.
Cholesterol is essential for cell physiology. Transport of the accessible pool of cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER) by ER-localized GRAMD1 proteins (GRAMD1a/1b/1c) contributes to cholesterol homeostasis. However, how cells detect accessible cholesterol within the PM remains unclear. We show that the GRAM domain of GRAMD1b, a coincidence detector for anionic lipids, including phosphatidylserine (PS), and cholesterol, possesses distinct but synergistic sites for sensing accessible cholesterol and anionic lipids. We find that a mutation within the GRAM domain of GRAMD1b that is associated with intellectual disability in humans specifically impairs cholesterol sensing. In addition, we identified another point mutation within this domain that enhances cholesterol sensitivity without altering its PS sensitivity. Cell-free reconstitution and cell-based assays revealed that the ability of the GRAM domain to sense accessible cholesterol regulates membrane tethering and determines the rate of cholesterol transport by GRAMD1b. Thus, cells detect the codistribution of accessible cholesterol and anionic lipids in the PM and fine-tune the non-vesicular transport of PM cholesterol to the ER via GRAMD1s.
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