Differential effects of transition metal cations on the conformation and biological activities of nerve growth factor

Direct effects of Zn2+ on the conformation and biological activity of nerve growth factor (NGF) have previously been described. Zn2+ binds to specific coordination sites within NGF and induces conformational changes within domains that participate in receptor recognition processes. Recent theoretical considerations indicate that other transition metal cations (particularly, Cu(2+)and Pd2+) are capable of forming similar complexes with NGF. Inactivation of NGF by transition metal cations is inhibitory to neuronal regeneration and sprouting, and can lead to cell death under conditions where NGF is required for survival in PC12 cells. In this study we investigated the influence of various metal ions on NGF conformation, geometry of NGF amino terminal peptide and NGF-mediated biological effects in FC12 cells. A number of metal ions (Zn2+, Cu2+ and Pd2+) alter NGF conformation in cell-free assays and inhibit NGF-mediated cell survival. Other metals have been shown to be either toxic to PC12 cells by mechanisms independent of NGF activity (e.g. Ag+, Hg2+) or non-toxic to the cells under conditions tested (e.g. Al3+, Cr3+). In conclusion, several metal cations are capable of inhibiting NGF activity, thereby blocking NGF-mediated cell survival and plasticity.