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Molecular basis of familial hypercholesterolaemia from structure of LDL receptor module

Author

Listed:
  • Deborah Fass

    (Howard Hughes Medical Institute, Massachusetts Institute of Technology
    Whitehead Institute for Biomedical Research, Nine Cambridge Center)

  • Stephen Blacklow

    (Howard Hughes Medical Institute, Massachusetts Institute of Technology
    Whitehead Institute for Biomedical Research, Nine Cambridge Center
    Stanford University>)

  • Peter S. Kim

    (Howard Hughes Medical Institute, Massachusetts Institute of Technology
    Whitehead Institute for Biomedical Research, Nine Cambridge Center)

  • James M. Berger

    (Whitehead Institute for Biomedical Research, Nine Cambridge Center)

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.

Suggested Citation

  • Deborah Fass & Stephen Blacklow & Peter S. Kim & James M. Berger, 1997. "Molecular basis of familial hypercholesterolaemia from structure of LDL receptor module," Nature, Nature, vol. 388(6643), pages 691-693, August.
    • Handle: RePEc:nat:nature:v:388:y:1997:i:6643:d:10.1038_41798
    DOI: 10.1038/41798
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    Cited by:

    1. Duanfang Cao & Bingting Ma & Ziyi Cao & Xiaoyu Xu & Xinzheng Zhang & Ye Xiang, 2024. "The receptor VLDLR binds Eastern Equine Encephalitis virus through multiple distinct modes," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Pan Yang & Wanyu Li & Xiaoyi Fan & Junhua Pan & Colin J. Mann & Haley Varnum & Lars E. Clark & Sarah A. Clark & Adrian Coscia & Himanish Basu & Katherine Nabel Smith & Vesna Brusic & Jonathan Abraham, 2024. "Structural basis for VLDLR recognition by eastern equine encephalitis virus," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Hongming Ma & Lucas J. Adams & Saravanan Raju & Alan Sariol & Natasha M. Kafai & Hana Janova & William B. Klimstra & Daved H. Fremont & Michael S. Diamond, 2024. "The low-density lipoprotein receptor promotes infection of multiple encephalitic alphaviruses," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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