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 或巨蛋白）是系统发育上保守的巨型 LDL 受体相关蛋白亚家族的代表，其在内吞作用中发挥作用，与肾脏和大脑疾病有关。在这里，我们报告了从小鼠肾脏分离的 LRP2 在细胞外和内体 pH 值下的高分辨率冷冻电镜结构。这些结构揭示了LRP2是一种分子机器，它采用一种在细胞表面进行配体结合并在内体中进行配体脱落的构象。 LRP2 形成同型二聚体，其构象转变由同型二聚体和原聚体内界面上的 pH 敏感位点控制。人类 LRP2 有害错义变异的一个子集似乎会损害同二聚体的组装。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，并表明同二聚化是LRP受体亚家族的保守特征。