Structures of LRP2 reveal a molecular machine for endocytosis

The low-density lipoprotein (LDL) receptor-related protein 2 (LRP2 or megalin) is representative of the phylogeneticallyconserved subfamily of giant LDL receptor-related proteins, which function in endocytosis and are implicated in diseases of thekidney and brain. Here, we report high-resolution cryoelectron microscopy structures of LRP2 isolated from mouse kidney, atextracellular and endosomal pH. The structures reveal LRP2 to be a molecular machine that adopts a conformation for ligandbinding at the cell surface and for ligand shedding in the endosome. LRP2 forms a homodimer, the conformational transformationof which is governed by pH-sensitive sites at both homodimer and intra-protomer interfaces. A subset of LRP2 deleteriousmissense variants in humans appears to impair homodimer assembly. These observations lay the foundation for furtherunderstanding the function and mechanism of LDL receptors and implicate homodimerization as a conserved feature of the LRPreceptor subfamily.