Abstract
The low-density lipoprotein receptor (LDLR) is responsible for the uptake of cholesterol-containing lipoprotein particles into cells1,2. The amino-terminal region of LDLR, which consists of seven tandemly repeated, ∼40-amino-acid, cysteine-rich modules (LDL-A modules), mediates binding to lipoproteins3,4. LDL-A modules are biologically ubiquitous domains, found in over 100 proteins in the sequence database5. The structure of ligand-binding repeat 5 (LR5) of the LDLR, determined to 1.7 å resolution by X-ray crystallography and presented here, contains a calcium ion coordinated by acidic residues that lie at the carboxy-terminal end of the domain and are conserved among LDL-A modules. Naturally occurring point mutations found in patients with the disease familial hypercholesterolaemia6 alter residues that directly coordinate Ca2+or that serve as scaffolding residues of LR5.
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Acknowledgements
We thank S. J. Gamblin for technical advice and discussions. J.M.B. is a Whitehead Fellow and acknowledges support from the W. M. Keck Foundation. This research utilized the W. M. Keck Foundation X-ray Crystallography Facility at the Whitehead Institute, and was supported by an NIH grant (to R. D. Rosenberg) from the Program of Excellence in Molecular Biology.
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Fass, D., Blacklow, S., Kim, P. et al. Molecular basis of familial hypercholesterolaemia from structure of LDL receptor module. Nature 388, 691–693 (1997). https://doi.org/10.1038/41798
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DOI: https://doi.org/10.1038/41798
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