Structures of LRP2 reveal a molecular machine for endocytosis.
Cell
; 186(4): 821-836.e13, 2023 02 16.
Article
en En
| MEDLINE
| ID: mdl-36750096
ABSTRACT
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.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Proteína 2 Relacionada con Receptor de Lipoproteína de Baja Densidad
/
Endocitosis
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cell
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos