Molecular basis of accessible plasma membrane cholesterol recognition by the GRAM domain of GRAMD1b
| Autor: | Yasunori Saheki, Dennis Dharmawan, Bilge Ercan, Dylan Hong Zheng Koh, Tomoki Naito |
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| Přispěvatelé: | Lee Kong Chian School of Medicine (LKCMedicine) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cell physiology
GRAM domain Lipid Sensor membrane contact sites Phosphatidylserines Biology Endoplasmic Reticulum plasma membrane medicine.disease_cause Article General Biochemistry Genetics and Molecular Biology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Protein Domains Cell Line Tumor Intellectual Disability Sense (molecular biology) medicine Humans Point Mutation Genetic Predisposition to Disease Medicine [Science] Membrane & Intracellular Transport Molecular Biology 030304 developmental biology 0303 health sciences Mutation General Immunology and Microbiology Cholesterol General Neuroscience Endoplasmic reticulum Point mutation Cell Membrane Membrane Proteins cholesterol Biological Transport Articles Phosphatidylserine Metabolism Membrane Amino Acid Substitution chemistry Biochemistry lipid sensor lipids (amino acids peptides and proteins) 030217 neurology & neurosurgery HeLa Cells |
| Zdroj: | The EMBO Journal |
| Popis: | 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. The GRAM domain of GRAMD1b senses cholesterol and anionic lipids present within the inner leaflet of the plasma membrane through distinct recognition sites, and thereby modulates ER‐PM tethering and cholesterol transport. |
| Databáze: | OpenAIRE |
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