GRAMD1-mediated accessible cholesterol sensing and transport

Cholesterol, an essential lipid for cell signaling and structural integrity of cellular membranes, is highly enriched in the plasma membrane (PM). However, the regulatory mechanisms that control its biosynthesis and uptake both reside in the endoplasmic reticulum (ER). Thus, the ER needs to constant...

Full description

Saved in:
Bibliographic Details
Main Authors: Naito, Tomoki, Saheki, Yasunori
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
Format: Article
Language:English
Published: 2022
Subjects:
Online Access:https://hdl.handle.net/10356/162676
Tags: Add Tag
No Tags, Be the first to tag this record!
Institution: Nanyang Technological University
Language: English
id sg-ntu-dr.10356-162676
record_format dspace
spelling sg-ntu-dr.10356-1626762022-11-03T08:03:20Z GRAMD1-mediated accessible cholesterol sensing and transport Naito, Tomoki Saheki, Yasunori Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Phosphatidylserine Non-Vesicular Lipid Transport Cholesterol, an essential lipid for cell signaling and structural integrity of cellular membranes, is highly enriched in the plasma membrane (PM). However, the regulatory mechanisms that control its biosynthesis and uptake both reside in the endoplasmic reticulum (ER). Thus, the ER needs to constantly monitor the levels of PM cholesterol. This is in part mediated by regulated transport of a biochemically defined pool of cholesterol, termed "accessible" cholesterol, from the PM to the ER via evolutionarily conserved ER-anchored lipid transfer proteins, the GRAMD1s/Asters (GRAMD1a/1b/1c) (Lam/Ltc proteins in yeast). GRAMD1s possess cytosolically exposed GRAM domain and StART-like domain followed by a transmembrane ER anchor. They form homo- and hetero-meric complexes and move to the contacts formed between the ER and the PM by sensing a transient expansion of the accessible pool of cholesterol in the PM via the GRAM domain and facilitate its extraction and transport to the ER via the StART-like domain. The GRAMD1b GRAM domain possesses distinct, but synergistic sites, for recognizing accessible cholesterol and anionic lipids, including phosphatidylserine, within the PM. This property of the GRAM domain contributes to regulated tethering of the PM to ER membrane where GRAMD1s are anchored and fine-tunes StART-like domain-dependent accessible cholesterol transport. Thus, cells use GRAMD1s to sense the levels of cholesterol in the PM and regulate transport of accessible PM cholesterol to the ER in order to maintain cholesterol homeostasis. Ministry of Education (MOE) This work was supported in part by the Ministry of Education, Singapore, under its Academic Research Fund Tier 2 Award (MOE2017-T2-2-001), a Nanyang Assistant Professorship (NAP), and a Lee Kong Chian School of Medicine startup grant (LKCMedicine-SUG) to Y.S. T.N. was supported by a fellowship from the Japanese Society for Promotion of Science. 2022-11-03T08:03:20Z 2022-11-03T08:03:20Z 2021 Journal Article Naito, T. & Saheki, Y. (2021). GRAMD1-mediated accessible cholesterol sensing and transport. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1866(8), 158957-. https://dx.doi.org/10.1016/j.bbalip.2021.158957 0167-4889 https://hdl.handle.net/10356/162676 10.1016/j.bbalip.2021.158957 33932585 2-s2.0-85105303601 8 1866 158957 en MOE2017-T2-2-001 Biochimica et Biophysica Acta (BBA) - Molecular Cell Research © 2021 Elsevier B.V. All rights reserved.
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Medicine
Phosphatidylserine
Non-Vesicular Lipid Transport
spellingShingle Science::Medicine
Phosphatidylserine
Non-Vesicular Lipid Transport
Naito, Tomoki
Saheki, Yasunori
GRAMD1-mediated accessible cholesterol sensing and transport
description Cholesterol, an essential lipid for cell signaling and structural integrity of cellular membranes, is highly enriched in the plasma membrane (PM). However, the regulatory mechanisms that control its biosynthesis and uptake both reside in the endoplasmic reticulum (ER). Thus, the ER needs to constantly monitor the levels of PM cholesterol. This is in part mediated by regulated transport of a biochemically defined pool of cholesterol, termed "accessible" cholesterol, from the PM to the ER via evolutionarily conserved ER-anchored lipid transfer proteins, the GRAMD1s/Asters (GRAMD1a/1b/1c) (Lam/Ltc proteins in yeast). GRAMD1s possess cytosolically exposed GRAM domain and StART-like domain followed by a transmembrane ER anchor. They form homo- and hetero-meric complexes and move to the contacts formed between the ER and the PM by sensing a transient expansion of the accessible pool of cholesterol in the PM via the GRAM domain and facilitate its extraction and transport to the ER via the StART-like domain. The GRAMD1b GRAM domain possesses distinct, but synergistic sites, for recognizing accessible cholesterol and anionic lipids, including phosphatidylserine, within the PM. This property of the GRAM domain contributes to regulated tethering of the PM to ER membrane where GRAMD1s are anchored and fine-tunes StART-like domain-dependent accessible cholesterol transport. Thus, cells use GRAMD1s to sense the levels of cholesterol in the PM and regulate transport of accessible PM cholesterol to the ER in order to maintain cholesterol homeostasis.
author2 Lee Kong Chian School of Medicine (LKCMedicine)
author_facet Lee Kong Chian School of Medicine (LKCMedicine)
Naito, Tomoki
Saheki, Yasunori
format Article
author Naito, Tomoki
Saheki, Yasunori
author_sort Naito, Tomoki
title GRAMD1-mediated accessible cholesterol sensing and transport
title_short GRAMD1-mediated accessible cholesterol sensing and transport
title_full GRAMD1-mediated accessible cholesterol sensing and transport
title_fullStr GRAMD1-mediated accessible cholesterol sensing and transport
title_full_unstemmed GRAMD1-mediated accessible cholesterol sensing and transport
title_sort gramd1-mediated accessible cholesterol sensing and transport
publishDate 2022
url https://hdl.handle.net/10356/162676
_version_ 1749179219009601536