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

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

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.

1756-5901
914-924
Brayshaw, Lewis L.
ec91fdf0-fc24-4ebf-8d85-2ee4e675e432
Smith, Rosanna C.G.
1fe5586f-92e9-4658-bd55-cd3eaa176b66
Badaoui, Magd
aa481163-c298-49c7-9a61-a03d26d2cd27
Irving, James A.
6eb01099-a3d7-4f40-8b9b-842feb242efd
Price, Stephen R.
b8c51bbd-a3c1-421e-94af-62041e861ee2
Brayshaw, Lewis L.
ec91fdf0-fc24-4ebf-8d85-2ee4e675e432
Smith, Rosanna C.G.
1fe5586f-92e9-4658-bd55-cd3eaa176b66
Badaoui, Magd
aa481163-c298-49c7-9a61-a03d26d2cd27
Irving, James A.
6eb01099-a3d7-4f40-8b9b-842feb242efd
Price, Stephen R.
b8c51bbd-a3c1-421e-94af-62041e861ee2

Brayshaw, Lewis L., Smith, Rosanna C.G., Badaoui, Magd, Irving, James A. and Price, Stephen R. (2019) Lanthanides compete with calcium for binding to cadherins and inhibit cadherin-mediated cell adhesion. Metallomics, 11 (5), 914-924. (doi:10.1039/c8mt00317c).

Record type: Article

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.

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More information

Accepted/In Press date: 20 February 2019
e-pub ahead of print date: 8 March 2019

Identifiers

Local EPrints ID: 431606
URI: http://eprints.soton.ac.uk/id/eprint/431606
ISSN: 1756-5901
PURE UUID: 651b9a16-e173-47d4-adc2-eafb66d00cc5

Catalogue record

Date deposited: 11 Jun 2019 16:30
Last modified: 07 Oct 2020 00:16

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