Division of Nephrology, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY 10027, USA.
Cell. 2023 Feb 16;186(4):821-836.e13. doi: 10.1016/j.cell.2023.01.016. Epub 2023 Feb 6.
The low-density lipoprotein (LDL) receptor-related protein 2 (LRP2 or megalin) is representative of the phylogenetically conserved subfamily of giant LDL receptor-related proteins, which function in endocytosis and are implicated in diseases of the kidney and brain. Here, we report high-resolution cryoelectron microscopy structures of LRP2 isolated from mouse kidney, at extracellular and endosomal pH. The structures reveal LRP2 to be a molecular machine that adopts a conformation for ligand binding at the cell surface and for ligand shedding in the endosome. LRP2 forms a homodimer, the conformational transformation of which is governed by pH-sensitive sites at both homodimer and intra-protomer interfaces. A subset of LRP2 deleterious missense variants in humans appears to impair homodimer assembly. These observations lay the foundation for further understanding the function and mechanism of LDL receptors and implicate homodimerization as a conserved feature of the LRP receptor subfamily.
低密度脂蛋白（LDL）受体相关蛋白 2（LRP2 或巨球蛋白）是进化上保守的巨型 LDL 受体相关蛋白亚家族的代表，该亚家族在细胞内吞作用中发挥作用，并与肾脏和大脑疾病有关。在这里，我们报道了从小鼠肾脏中分离出的 LRP2 的高分辨率冷冻电子显微镜结构，分别在细胞外和内涵体 pH 值条件下。这些结构揭示了 LRP2 是一种分子机器，它在细胞表面形成配体结合的构象，在内体中形成配体脱落的构象。LRP2 形成同源二聚体，其构象转化受同源二聚体和单体内界面上的 pH 敏感位点控制。人类中一组 LRP2 的有害错义变异似乎会损害同源二聚体的组装。这些观察结果为进一步了解 LDL 受体的功能和机制奠定了基础，并暗示同源二聚化是 LRP 受体亚家族的一个保守特征。
