Abstract
The low-density lipoprotein receptor (LDLR) is the primary mechanism for uptake of cholesterol-carrying particles into cells. The region of the LDLR implicated in receptor recycling and lipoprotein release at low pH contains a pair of calcium-binding EGF-like modules, followed by a series of six YWTD repeats and a third EGF-like module. The crystal structure at 1.5 Å resolution of a receptor fragment spanning the YWTD repeats and its two flanking EGF modules reveals that the YWTD repeats form a six-bladed β-propeller that packs tightly against the C-terminal EGF module, whereas the EGF module that precedes the propeller is disordered in the crystal. Numerous point mutations of the LDLR that result in the genetic disease familial hypercholesterolemia (FH) alter side chains that form conserved packing and hydrogen bonding interactions in the interior and between propeller blades. A second subset of FH mutations are located at the interface between the propeller and the C-terminal EGF module, suggesting a structural requirement for maintaining the integrity of the interdomain interface.
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Acknowledgements
We thank J.-H. Wang for helpful discussions, F. Poy for assistance with computer graphics, S.E. Choe for the program homology, and C. Heaton and the staff at CHESS for assistance with synchotron data collection on beamline A1. This research is supported by NIH grants to S.C.B, T.A.S. and M.J.E. S.C.B. is a Pew Scholar in the Biomedical Sciences. This work is based upon research conducted at the Cornell High Energy Synchrotron Source (CHESS), which is supported by the National Science Foundation, using the Macromolecular Diffraction at CHESS (MacCHESS) facility, which is supported by the National Institutes of Health.
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Jeon, H., Meng, W., Takagi, J. et al. Implications for familial hypercholesterolemia from the structure of the LDL receptor YWTD-EGF domain pair. Nat Struct Mol Biol 8, 499–504 (2001). https://doi.org/10.1038/88556
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DOI: https://doi.org/10.1038/88556
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