Research: Cryo-EM structures elucidate the multiligand receptor nature of megalin

Proc Natl Acad Sci U S A

. 2024 May 28;121(22):e2318859121.

 doi: 10.1073/pnas.2318859121. Epub 2024 May 21. https://pubmed.ncbi.nlm.nih.gov/38771880/

Cryo-EM structures elucidate the multiligand receptor nature of megalin

Sawako Goto # 1Akihisa Tsutsumi # 2Yongchan Lee 3Michihiro Hosojima 4Hideyuki Kabasawa 4Koichi Komochi 4Satoru Nagatoishi 5Kazuya Takemoto 1Kouhei Tsumoto 6Tomohiro Nishizawa 3Masahide Kikkawa 2Akihiko Saito 1

Affiliations expand

Abstract

Megalin (low-density lipoprotein receptor-related protein 2) is a giant glycoprotein of about 600 kDa, mediating the endocytosis of more than 60 ligands, including those of proteins, peptides, and drug compounds [S. Goto, M. Hosojima, H. Kabasawa, A. Saito, Int. J. Biochem. Cell Biol. 157, 106393 (2023)]. It is expressed predominantly in renal proximal tubule epithelial cells, as well as in the brain, lungs, eyes, inner ear, thyroid gland, and placenta. Megalin is also known to mediate the endocytosis of toxic compounds, particularly those that cause renal and hearing disorders [Y. Hori et al.J. Am. Soc. Nephrol. 28, 1783-1791 (2017)]. Genetic megalin deficiency causes Donnai-Barrow syndrome/facio-oculo-acoustico-renal syndrome in humans. However, it is not known how megalin interacts with such a wide variety of ligands and plays pathological roles in various organs. In this study, we elucidated the dimeric architecture of megalin, purified from rat kidneys, using cryoelectron microscopy. The maps revealed the densities of endogenous ligands bound to various regions throughout the dimer, elucidating the multiligand receptor nature of megalin. We also determined the structure of megalin in complex with receptor-associated protein, a molecular chaperone for megalin. The results will facilitate further studies on the pathophysiology of megalin-dependent multiligand endocytic pathways in multiple organs and will also be useful for the development of megalin-targeted drugs for renal and hearing disorders, Alzheimer’s disease [B. V. Zlokovic et al.Proc. Natl. Acad. Sci. U.S.A. 93, 4229-4234 (1996)], and other illnesses.

Keywords: cryoelectron microscopy; endocytosis; ligand binding; megalin; proximal tubule.

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