8EM4

Cryo-EM structure of LRP2 at pH 7.5

Summary for 8EM4

• Entry DOI: 10.2210/pdb8em4/pdb
• EMDB information: 28233 28241 28242 28243 28250
• Descriptor: Low-density lipoprotein receptor-related protein 2, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-galactopyranose, ... (5 entities in total)
• Functional Keywords: lrp2, megalin, gp330, endocytosis, membrane protein
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 2
• Total formula weight: 1063617.07

Authors

Beenken, A.,Cerutti, G.,Brasch, J.,Fitzpatrick, A.W.,Barasch, J.,Shapiro, L. (deposition date: 2022-09-26, release date: 2023-02-08, Last modification date: 2024-11-13)

Primary citation

Beenken, A.,Cerutti, G.,Brasch, J.,Guo, Y.,Sheng, Z.,Erdjument-Bromage, H.,Aziz, Z.,Robbins-Juarez, S.Y.,Chavez, E.Y.,Ahlsen, G.,Katsamba, P.S.,Neubert, T.A.,Fitzpatrick, A.W.P.,Barasch, J.,Shapiro, L.
Structures of LRP2 reveal a molecular machine for endocytosis.
Cell, 186:821-, 2023

PubMed 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.

PubMed: 36750096
DOI: 10.1016/j.cell.2023.01.016

Experimental method

ELECTRON MICROSCOPY (2.83 Å)