Structures of LRP2 reveal a molecular machine for endocytosis.
CD91
LDL
LRP1
LRP2
cryo-EM
endocytosis
megalin
pH-sensitive
proteinuria
recycling
Journal
Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066
Informations de publication
Date de publication:
16 02 2023
16 02 2023
Historique:
received:
11
10
2022
revised:
29
11
2022
accepted:
10
01
2023
pubmed:
8
2
2023
medline:
25
2
2023
entrez:
7
2
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 36750096
pii: S0092-8674(23)00046-6
doi: 10.1016/j.cell.2023.01.016
pmc: PMC9993842
mid: NIHMS1875572
pii:
doi:
Substances chimiques
Ligands
0
Low Density Lipoprotein Receptor-Related Protein-2
0
LRP2 protein, human
0
Lrp2 protein, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
821-836.e13Subventions
Organisme : NINDS NIH HHS
ID : U01 NS110438
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK124667
Pays : United States
Organisme : NIDDK NIH HHS
ID : U54 DK104309
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK108741
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR027990
Pays : United States
Informations de copyright
Copyright © 2023 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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