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

Abstract

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 p75NTR. We demonstrate here that Zn2+ alters the conformation of NGF, rendering it unable to bind to p75NTR 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.

Zinc inhibits p75NTR-mediated apoptosis in chick neural retina

“…30 Here we demonstrate that Zn 2+ blocks the binding of 125 I-NGF to p75 NTR in dissociated ED5.5 retinal cells. As p75 NTR is the only neurotrophin receptor which interacts with NGF in these cells, we could use both total binding and chemical cross-linking analysis to evaluate the dose response profile of Zn 2+ .…”

“…Zn 2+ inhibits binding of NGF to p75 NTR Previously, we proposed that Zn 2+ alters the conformation of NGF, 30,32 and inhibits binding to p75 NTR , in a low affinity state. 30 Here we demonstrate that Zn 2+ blocks the binding of 125 I-NGF to p75 NTR in dissociated ED5.5 retinal cells.…”

“…Theoretical studies have predicted that the ability of NGF to bind to p75 NTR can be attenuated in the presence of Zn 2+ and other transition metal cations, 32 and Zn 2+ blocks binding to`low affinity' p75 NTR . 30 These results led to the hypothesis that Zn 2+ may block the pro-apoptotic effects of NGF. In this study we characterize the effects of Zn 2+ on the binding of NGF to p75 NTR and p75 NTR -mediated apoptosis in embryonic day 5.5 (ED5.5) chick retinal cells.…”

“…24 Zinc has previously been shown to block NGF-mediated neurite outgrowth in chick dorsal root ganglia (DRG), and rescue pheochromocytoma (PC12) cells from oxidative stress. 30,31 Both effects are mediated via the TrkA receptor. Theoretical studies have predicted that the ability of NGF to bind to p75 NTR can be attenuated in the presence of Zn 2+ and other transition metal cations, 32 and Zn 2+ blocks binding to`low affinity' p75 NTR .…”

Zinc‐induced damage to carp (Cyprinus carpio L.) erythrocytes in vitro

“…The most important antioxidant enzymes are superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (Px-GSH) [9]. The non-enzymic free-radical scavengers are represented by glutathione, vitamins E, C, A and carotenes [8,21]. Two types of superoxide dismutase (EC 1.15.1.1) are known from fish, one containing copper and zinc (Cu,Zn-SOD), the other manganese (Mn-SOD) [15].…”