Lee Kong Chian School of Medicine, Nanyang Technological University, 308232, Singapore.
Lee Kong Chian School of Medicine, Nanyang Technological University, 308232, Singapore; Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan.
Biochim Biophys Acta Mol Cell Biol Lipids. 2021 Aug;1866(8):158957. doi: 10.1016/j.bbalip.2021.158957. Epub 2021 Apr 28.
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.
胆固醇是细胞信号转导和细胞膜结构完整性所必需的脂质，在质膜（PM）中高度富集。然而，控制其生物合成和摄取的调节机制都存在于内质网（ER）中。因此，内质网需要不断监测 PM 胆固醇的水平。这在一定程度上是通过调节性地将称为“可及”胆固醇的生物化学定义的胆固醇池从 PM 运输到 ER 来介导的，这是通过进化上保守的 ER 锚定脂质转移蛋白，即 GRAMD1s/Asters（GRAMD1a/1b/1c）（酵母中的 Lam/Ltc 蛋白）来实现的。GRAMD1s 具有暴露在细胞质中的 GRAM 结构域和 StART 样结构域，后面是跨膜 ER 锚。它们形成同型和异型复合物，并通过感知 PM 中可及胆固醇池的短暂扩张，通过 GRAM 结构域移动到 ER 和 PM 之间形成的接触点，通过 StART 样结构域促进其提取和运输到 ER。GRAMD1b 的 GRAM 结构域具有识别 PM 中可及胆固醇和阴离子脂质（包括磷脂酰丝氨酸）的独特但协同的位点。这种 GRAM 结构域的特性有助于将 PM 有条件地锚定在 GRAMD1s 锚定的 ER 膜上，并微调 StART 样结构域依赖的可及胆固醇运输。因此，细胞利用 GRAMD1s 来感知 PM 中胆固醇的水平，并调节可及 PM 胆固醇向 ER 的运输，以维持胆固醇的体内平衡。
