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LDL-receptor structure

Calcium cages, acid baths and recycling receptors

Nature volume 388, pages 629–630 (1997)Cite this article

How would you design a 40-amino-acid peptide that is rigid enough to survive hundreds of acid baths at 10-minute intervals, yet adaptable enough to bind unrelated macromolecules with high affinity at pH 7.4, and discharge them rapidly at pH 5.5? If you answered “Put in three disulphide bonds and an octahedral calcium cage”, you were right, but too late — nature invented this peptide more than 500 million years ago, and has used it repeatedly ever since. The peptide in question is the ligand-binding repeat of the low-density lipoprotein receptor (LDLR), and the basis for its stability is revealed in elegant detail by the crystallographic studies of Fass et al.1 on page 691 of this issue.

The disulphide bridges are not the only reason for the stability of the LDLR. Ligand binding is destroyed by metal chelators and restored by calcium4. Fass et al.1 explain this by showing that each repeat contains a single Ca2+ ion trapped in an octahedral cage that is formed by four conserved acidic residues plus two nearby carbonyl oxygens. Evidence that this Ca2+ cage stabilizes the LDLR is consistent with previous studies5 of patients with familial hypercholesterolaemia, who have mutations that destroy LDLR function. The LDLR normally removes cholesterol-carrying lipoproteins from blood, so these patients have high levels of blood cholesterol, and suffer from heart attacks at a young age. More than 250 LDLR mutations have been described, among which about 50 are point mutations that substitute individual amino acids in the seven repeats of the ligandbinding domain5. Many of the point mutations replace the residues of the Ca2+ cage, thereby destabilizing the receptor.

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Figure 1: Members of the low-density lipoprotein receptor (LDLR) gene family share extracellular sequences (ligand-binding repeats and epidermal growth factor (EGF)-precursor domains, with or without O-linked sugar domains), transmembrane orientation, and cytoplasmic NPxY sequences that mediate the internalization of coated pits.

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Authors and Affiliations

  1. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, 75235>, Texas, USA

    Michael S. Brown, Joachim Herz & Joseph L. Goldstein

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  1. Michael S. Brown
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  2. Joachim Herz
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  3. Joseph L. Goldstein
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Brown, M., Herz, J. & Goldstein, J. Calcium cages, acid baths and recycling receptors. Nature 388, 629–630 (1997). https://doi.org/10.1038/41672

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