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.
Highlights
Lanthanides are widely used in medicine and biological research
We investigated the binding of the lanthanide Tb3+ to two classical cadherins with fundamental functions in embryo development and tumour metastasis, E-cadherin and N-cadherin
Similar results were obtained in cell aggregation assays in the presence of another lanthanide, Gd3+, suggesting that cadherin-mediated cell adhesion is inhibited by Ca2+-mimicking lanthanides (Fig. S2, Electronic supplementary information (ESI)†)
Summary
Lanthanides are widely used in medicine and biological research. A unique feature of lanthanides is their ability to mimic calcium in biological processes and the binding of lanthanides is known to induce a range of effects in calcium-binding proteins. X-ray crystal structures indicate that three Ca2+ ions can bind at each of the four linker regions and that the cadherin protein gradually attains its functional conformation as Ca2+ ions bind to the 12 binding sites.[29,30,31] Successive Ca2+-binding results in the precise relative positioning of EC domains and imparts rigidity and curvature onto the cadherin molecule which is an essential feature for cadherin function.[32,33,34] as Ca2+ ions bind to a cadherin molecule, the binding affinity for successive Ca2+ ions increases due to cooperativity in binding and conformational changes which are transmitted distally along the cadherin.[35,36] Whether lanthanides can bind cadherins and effectively replace calcium in supporting cadherin function has not been comprehensively investigated
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