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Implications for familial hypercholesterolemia from the structure of the LDL receptor YWTD-EGF domain pair

Nature Structural Biology volume 8, pages 499–504 (2001)Cite this article

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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Figure 1: Domain organization, sequence alignment and electron density.
Figure 2: Overview of structure and features of propeller blades.
Figure 3: Complementarity in the interface between the YWTD propeller and E3.
Figure 4: Sites of FH mutations mapped onto the structure of the YWTD-EGF domain pair.

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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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  1. Hyesung Jeon, Wuyi Meng, Junichi Takagi and Timothy A. Springer: These authors contributed equally to this work.

Authors and Affiliations

  1. Brigham Women's Hospital and Harvard Medical School Department of Pathology, 75 Francis Street, Boston, 02115, Massachusetts, USA

    Hyesung Jeon & Stephen C. Blacklow

  2. Dana Farber Cancer Institute and Harvard Medical School Department of Biological Chemistry and Molecular Pharmacology, 44 Binney Street, Boston, 02115, Massachusetts, USA

    Wuyi Meng & Michael J. Eck

  3. Center for Blood Research and Harvard Medical School Department of Pathology, 200 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Junichi Takagi & Timothy A. Springer

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  1. Hyesung Jeon
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Correspondence to Stephen C. Blacklow.

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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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