Structures of LRP2 reveal a molecular machine for endocytosis.
Cell
; 186(4): 821-836.e13, 2023 02 16.
Article
in 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Low Density Lipoprotein Receptor-Related Protein-2
/
Endocytosis
Limits:
Animals
/
Humans
Language:
En
Journal:
Cell
Year:
2023
Document type:
Article
Affiliation country:
United States
Publication country:
EEUU
/
ESTADOS UNIDOS
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ESTADOS UNIDOS DA AMERICA
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EUA
/
UNITED STATES
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UNITED STATES OF AMERICA
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US
/
USA