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Lanthanides compete with calcium for binding to cadherins and inhibit cadherin-mediated cell adhesion

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Abstract

Lanthanides are rare-earth metals with a broad range of applications in biological research and medicine. In addition to their unique magnetic and spectroscopic properties, lanthanides are also effective mimics of calcium and can stimulate or inhibit the function of calcium-binding proteins. Cadherins are a large family of calcium-binding proteins that facilitate cell adhesion and play key roles in embryo development, tissue homeostasis and tumour metastasis. However, whether lanthanides can bind cadherins and functionally replace calcium binding has not been comprehensively explored. In this study, we investigated the effect of lanthanide binding on cadherin structure and function using terbium, which is a commonly used lanthanide for protein spectroscopy and a proposed anti-cancer agent. We demonstrate that terbium can compete with calcium for binding to calcium-binding sites in cadherins. Terbium binding to cadherins abolished their cell adhesive activity and rendered cadherins sensitive to proteolysis by trypsin. Molecular dynamics simulations indicate that replacement of calcium by terbium results in structural rearrangements and increases the flexibility of the cadherin ectodomain. These changes in structure and dynamics are likely to underlie the inability of lanthanide-bound cadherins to support cell adhesion. Taken together, our findings further knowledge on lanthanide interactions with calcium-binding proteins and provide new insight into the influence of metal chemistry on cadherin structure, dynamics and function.

Graphical abstract: Lanthanides compete with calcium for binding to cadherins and inhibit cadherin-mediated cell adhesion

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Publication details

The article was received on 02 Nov 2018, accepted on 20 Feb 2019 and first published on 08 Mar 2019


Article type: Paper
DOI: 10.1039/C8MT00317C
Citation: Metallomics, 2019, Advance Article
  • Open access: Creative Commons BY license
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    Lanthanides compete with calcium for binding to cadherins and inhibit cadherin-mediated cell adhesion

    L. L. Brayshaw, R. C. G. Smith, M. Badaoui, J. A. Irving and S. R. Price, Metallomics, 2019, Advance Article , DOI: 10.1039/C8MT00317C

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