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Structure paper

TitleCryo-EM structures elucidate the multiligand receptor nature of megalin.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 121, Issue 22, Page e2318859121, Year 2024
Publish dateMay 28, 2024
AuthorsSawako Goto / Akihisa Tsutsumi / Yongchan Lee / Michihiro Hosojima / Hideyuki Kabasawa / Koichi Komochi / Satoru Nagatoishi / Kazuya Takemoto / Kouhei Tsumoto / Tomohiro Nishizawa / Masahide Kikkawa / Akihiko Saito /
PubMed AbstractMegalin (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 ...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, , 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 , , 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 , , 4229-4234 (1996)], and other illnesses.
External linksProc Natl Acad Sci U S A / PubMed:38771880 / PubMed Central
MethodsEM (single particle)
Resolution3.2 - 4.2 Å
Structure data

EMDB-36663, PDB-8jut:
rat megalin RAP complex
Method: EM (single particle) / Resolution: 4.2 Å

EMDB-36664, PDB-8juu:
rat megalin
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-36692, PDB-8jx8:
rat megalin head
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-36693, PDB-8jx9:
rat megalin bodyA
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-36694, PDB-8jxa:
cryo-EM structure of rat megalin bodyB
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-36695: Cryo-EM structure of rat megalin wingA
PDB-8jxb: Cryo-EM structure of rat megalin wingAc
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-36696, PDB-8jxc:
rat megalin wingB
Method: EM (single particle) / Resolution: 3.7 Å

EMDB-36697, PDB-8jxd:
Cryo-EM structure of rat megalin leg
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-36698, PDB-8jxe:
rat megalin RAP complex head
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-36699, PDB-8jxf:
rat megalin RAP complex bodyA
Method: EM (single particle) / Resolution: 3.6 Å

EMDB-36700, PDB-8jxg:
rat megalin RAP complex bodyB
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-36701, PDB-8jxh:
rat megalin RAP complex wingA
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-36702, PDB-8jxi:
rat megalin RAP complex wingB
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-36703, PDB-8jxj:
rat megalin RAP complex leg
Method: EM (single particle) / Resolution: 3.9 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-A2G:
2-acetamido-2-deoxy-alpha-D-galactopyranose

ChemComp-CA:
Unknown entry

ChemComp-NI:
NICKEL (II) ION

Source
  • rattus norvegicus (Norway rat)
  • Rattus (rat)
KeywordsENDOCYTOSIS / endocytosis receptor

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