Cadmium Disruption of Neural Cadherin Dimerization
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Cadherins are calcium-dependent cell-adhesion proteins that are vital to the formation and maintenance of solid tissues. Neural (N-) Cadherin plays an essential role in early development processes such as angiogenesis and development of the neural plate. The prerequisite of calcium (Ca2+) binding for adhesion begs the question of whether other divalent cations could promote or inhibit dimer formation. Due to its ionic radius and chelation geometry, cadmium (Cd2+) has been shown to substitute for Ca2+ in select physiological processes. The studies described here evaluate whether Cd2+ binds to N-Cadherin as a heteroligand, thereby disrupting calcium-induced dimerization. Studies were also conducted to predict the effects of Cd2+ at relatively low Ca2+ concentration, as typical for excitatory neural synapses. This study features both experimental and numerical analysis of ligand binding and ligand-induced dimerization. The ligand binding constants resolved for calcium and cadmium indicated that cadmium binds to N-cadherin with ~4x higher affinity than that of calcium. Further, low levels of Cd2+ decrease dimer formation at calcium concentrations found at neurological synapses. Analysis shows that Cd2+ disrupts dimerization of N-Cadherin, consistent with its competition for the Ca2+-binding sites. Our observations of dimer disassembly in the presence of Cd2+ support the hypothesis that at very low levels, Cd2+ will have minimal effect on N-Cadherin mediated cell-adhesion in the body; however, Cd2+ at these same levels at excitatory synapses can disrupt cell adhesion and compromise normal neurological processes including the formation of memory and reflex stimulation.