{"@context":{"@vocab":"https://cir.nii.ac.jp/schema/1.0/","rdfs":"http://www.w3.org/2000/01/rdf-schema#","dc":"http://purl.org/dc/elements/1.1/","dcterms":"http://purl.org/dc/terms/","foaf":"http://xmlns.com/foaf/0.1/","prism":"http://prismstandard.org/namespaces/basic/2.0/","cinii":"http://ci.nii.ac.jp/ns/1.0/","datacite":"https://schema.datacite.org/meta/kernel-4/","ndl":"http://ndl.go.jp/dcndl/terms/","jpcoar":"https://github.com/JPCOAR/schema/blob/master/2.0/"},"@id":"https://cir.nii.ac.jp/crid/1360869855110589056.json","@type":"Article","productIdentifier":[{"identifier":{"@type":"DOI","@value":"10.1073/pnas.2318859121"}},{"identifier":{"@type":"URI","@value":"https://pnas.org/doi/pdf/10.1073/pnas.2318859121"}}],"resourceType":"学術雑誌論文(journal article)","dc:title":[{"@value":"Cryo-EM structures elucidate the multiligand receptor nature of megalin"}],"description":[{"type":"abstract","notation":[{"@value":"<jats:p>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,<jats:italic>Int. J. Biochem. Cell Biol.</jats:italic><jats:bold>157</jats:bold>, 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<jats:italic>et al.</jats:italic>,<jats:italic>J. Am. Soc. Nephrol.</jats:italic><jats:bold>28</jats:bold>, 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<jats:italic>et al.</jats:italic>,<jats:italic>Proc. Natl. Acad. Sci. U.S.A.</jats:italic><jats:bold>93</jats:bold>, 4229–4234 (1996)], and other illnesses.</jats:p>"}]}],"creator":[{"@id":"https://cir.nii.ac.jp/crid/1420564276160135296","@type":"Researcher","personIdentifier":[{"@type":"KAKEN_RESEARCHERS","@value":"10832884"},{"@type":"NRID","@value":"1000010832884"}],"foaf:name":[{"@value":"Sawako Goto"}],"jpcoar:affiliationName":[{"@value":"Department of Applied Molecular Medicine, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata City 951-8510, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380869855110589190","@type":"Researcher","foaf:name":[{"@value":"Akihisa Tsutsumi"}],"jpcoar:affiliationName":[{"@value":"Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380869855110589057","@type":"Researcher","foaf:name":[{"@value":"Yongchan Lee"}],"jpcoar:affiliationName":[{"@value":"Department of the Biological Membrane Dynamics, Graduate School of Medical Life Science, Yokohama City University, Yokohama 230-0045, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380869855110589058","@type":"Researcher","foaf:name":[{"@value":"Michihiro Hosojima"}],"jpcoar:affiliationName":[{"@value":"Department of Clinical Nutrition Science, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata City 951-8510, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380869855110589060","@type":"Researcher","foaf:name":[{"@value":"Hideyuki Kabasawa"}],"jpcoar:affiliationName":[{"@value":"Department of Clinical Nutrition Science, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata City 951-8510, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380869855110589059","@type":"Researcher","foaf:name":[{"@value":"Koichi Komochi"}],"jpcoar:affiliationName":[{"@value":"Department of Clinical Nutrition Science, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata City 951-8510, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380869855110589189","@type":"Researcher","foaf:name":[{"@value":"Satoru Nagatoishi"}],"jpcoar:affiliationName":[{"@value":"Medical Device Development and Regulation Research Center, School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380869855110589184","@type":"Researcher","foaf:name":[{"@value":"Kazuya Takemoto"}],"jpcoar:affiliationName":[{"@value":"Department of Applied Molecular Medicine, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata City 951-8510, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380869855110589056","@type":"Researcher","foaf:name":[{"@value":"Kouhei Tsumoto"}],"jpcoar:affiliationName":[{"@value":"Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380869855110589188","@type":"Researcher","foaf:name":[{"@value":"Tomohiro Nishizawa"}],"jpcoar:affiliationName":[{"@value":"Department of the Biological Membrane Dynamics, Graduate School of Medical Life Science, Yokohama City University, Yokohama 230-0045, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380869855110589186","@type":"Researcher","foaf:name":[{"@value":"Masahide Kikkawa"}],"jpcoar:affiliationName":[{"@value":"Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan"}]},{"@id":"https://cir.nii.ac.jp/crid/1380869855110589187","@type":"Researcher","foaf:name":[{"@value":"Akihiko Saito"}],"jpcoar:affiliationName":[{"@value":"Department of Applied Molecular Medicine, Kidney Research Center, Niigata University Graduate School of Medical and Dental Sciences, Niigata City 951-8510, Japan"}]}],"publication":{"publicationIdentifier":[{"@type":"PISSN","@value":"00278424"},{"@type":"EISSN","@value":"10916490"}],"prism:publicationName":[{"@value":"Proceedings of the National Academy of Sciences"}],"dc:publisher":[{"@value":"Proceedings of the National Academy of Sciences"}],"prism:publicationDate":"2024-05-21","prism:volume":"121","prism:number":"22"},"reviewed":"false","dcterms:accessRights":"http://purl.org/coar/access_right/c_abf2","dc:rights":["https://creativecommons.org/licenses/by-nc-nd/4.0/"],"url":[{"@id":"https://pnas.org/doi/pdf/10.1073/pnas.2318859121"}],"createdAt":"2024-05-21","modifiedAt":"2024-11-19","project":[{"@id":"https://cir.nii.ac.jp/crid/1040289864809246976","@type":"Project","projectIdentifier":[{"@type":"KAKEN","@value":"21H05248"},{"@type":"JGN","@value":"JP21H05248"},{"@type":"URI","@value":"https://kaken.nii.ac.jp/grant/KAKENHI-PLANNED-21H05248/"}],"notation":[{"@language":"ja","@value":"クロススケールIn-cell cryo-ET技術の開発と上皮組織への応用"},{"@language":"en","@value":"Cross-scale in-cell cryo-electron tomography and its application to epithelium"}]},{"@id":"https://cir.nii.ac.jp/crid/1040291932577332224","@type":"Project","projectIdentifier":[{"@type":"KAKEN","@value":"22K16213"},{"@type":"JGN","@value":"JP22K16213"},{"@type":"URI","@value":"https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22K16213/"}],"notation":[{"@language":"ja","@value":"メガリンと腎毒性リガンドの結合様式とメガリン拮抗薬の薬理機序の立体構造学的解析"},{"@language":"en","@value":"Structural Analysis of the Binding Interaction Between Megalin and Nephrotoxic Ligands, and the Pharmacological Mechanism of Megalin Antagonists"}]}],"relatedProduct":[{"@id":"https://cir.nii.ac.jp/crid/1360011146398638080","@type":"Article","relationType":["references"],"jpcoar:relatedTitle":[{"@value":"Quantitative proteomic analysis of distinct mammalian Mediator complexes using normalized spectral abundance 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