論文

国際誌
2024年5月28日

Cryo-EM structures elucidate the multiligand receptor nature of megalin.

Proceedings of the National Academy of Sciences of the United States of America
  • Sawako Goto
  • Akihisa Tsutsumi
  • Yongchan Lee
  • Michihiro Hosojima
  • Hideyuki Kabasawa
  • Koichi Komochi
  • Satoru Nagatoishi
  • Kazuya Takemoto
  • Kouhei Tsumoto
  • Tomohiro Nishizawa
  • Masahide Kikkawa
  • Akihiko Saito
  • 全て表示

121
22
開始ページ
e2318859121
終了ページ
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1073/pnas.2318859121

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.

リンク情報
DOI
https://doi.org/10.1073/pnas.2318859121
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/38771880
ID情報
  • DOI : 10.1073/pnas.2318859121
  • PubMed ID : 38771880

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