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

Cadherin de-adhesion: consequences and mechanisms

Cell-to-cell cadherin adhesions play an important role in regulating the behaviour of neural progenitor cells as well as providing the structural framework of the niche in which they reside. Cadherin de-adhesion can occur aberrantly and has significant consequences on the regulation of neural progenitor cells and disease progression. This work specifically investigated what are the consequences of cadherin de-adhesion on neural progenitor cell positioning and how changes in positioning affect neural progenitor cell maintenance. Cadherin de-adhesion was induced in the hindbrains of chick embryos through the expression of dominant negative N-cadherin and γ-catenin, two important components of cadherin adhesion. Cadherin de-adhesion caused the mispositioning of neural progenitor cells outside of the niche, this change in positioning resulted in diminished proliferation and activation of cell death. The results suggest cadherin adhesions control the positioning of neural progenitor cells and are a fundamental component of the neural progenitor cell niche. Cadherin de-adhesion also inhibited the induction of homeodomain expression in ventral neural progenitor cells, which is likely due to a reduction of notch signalling in the niche and subsequent de-sensitisation of neural progenitor cells to Shh. A model for cadherin adhesions as spatial regulators of neural progenitor cell maintenance is proposed. The mechanisms of how cadherin de-adhesion occurs remain poorly described and this work explored the significance of changes in calcium-cadherin binding in cadherin de-adhesion. This work demonstrated that an extracellular acidic pH alters calcium-cadherin binding interactions, which negatively affects cadherin-mediated cell adhesion. Additionally, cadherin calcium-binding sites are shown to be promiscuous to other metal ions but cadherin function is not. Cell aggregation, trypsin protection, and FRET binding assays demonstrated that the close calcium analogue, the trivalent ion of the lanthanide element terbium, can bind to cadherin calcium-binding sites but cannot induce rigid and adhesive cadherin molecules. Trivalent terbium, which has been previously proposed as an anti-cancer agent, therefore inhibits cadherin-mediated cell adhesion by competitive binding with calcium at cadherin calcium-binding sites. Together, the results reveal how changes to calcium-cadherin binding interactions affect cadherin adhesion and the possible significance of such changes to cadherin de-adhesion in cancer is described