Zinc alters conformation and inhibits biological activities of nerve growth factor and related neurotrophins

A role for Zn2+ in a variety of neurological conditions such as stroke, epilepsy and Alzheimer's disease has been postulated. In many instances, susceptible neurons are located in regions rich In Zn2+ where nerve growth factor (NGF) levels rise as a result of insult. Although the interaction of Zn2+ with this neurotrophin has previously been suggested, the direct actions of the ion on NGF function have not been explored. Molecular modeling studies predict that Zn2+ binding to NGF will Induce structural changes within domains of this neurotrophin that participate in the recognition of TrkA and p75(NTR). We demonstrate here that Zn2+ alters the conformation of NGF, rendering it unable to bind to p75(NTR) or TrkA receptors or to activate signal transduction pathways and biological outcomes normally induced by this protein. Similar actions of Zn2+ are also observed with other members of the NGF family, suggesting a modulatory role for this metal ion in neurotrophin function.