Structure of the LDL Receptor Extracellular Domain at Endosomal pH

The low-density lipoprotein receptor mediates cholesterol homeostasis through endocytosis of lipoproteins. It discharges its ligand in the endosome at pH < 6. In the crystal structure at pH = 5.3, the ligand-binding domain (modules R2 to R7) folds back as an arc over the epidermal growth factor p...

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Veröffentlicht in:Science (American Association for the Advancement of Science) 2002-12, Vol.298 (5602), p.2353-2358
Hauptverfasser: Rudenko, Gabby, Henry, Lisa, Henderson, Keith, Ichtchenko, Konstantin, Brown, Michael S., Goldstein, Joseph L., Deisenhofer, Johann
Format: Artikel
Sprache:eng
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Zusammenfassung:The low-density lipoprotein receptor mediates cholesterol homeostasis through endocytosis of lipoproteins. It discharges its ligand in the endosome at pH < 6. In the crystal structure at pH = 5.3, the ligand-binding domain (modules R2 to R7) folds back as an arc over the epidermal growth factor precursor homology domain (the modules A, B, β propeller, and C). The modules R4 and R5, which are critical for lipoprotein binding, associate with the β propeller via their calcium-binding loop. We propose a mechanism for lipoprotein release in the endosome whereby the β propeller functions as an alternate substrate for the ligand-binding domain, binding in a calcium-dependent way and promoting lipoprotein release.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.1078124