Zinc Binding to S100B Affords Regulation of Trace Metal Homeostasis and Excitotoxicity in the Brain

Abstract

Neuronal metal ions such as zinc are essential for brain function. In particular synaptic processes are tightly related to metal and protein homeostasis, for example through extracellular metal-binding proteins. One such protein is neuronal S100B, a calcium and zinc binding damage-associated molecular pattern (DAMP), whose chronic upregulation is associated with aging, Alzheimer’s disease (AD), motor neuron disease and traumatic brain injury (TBI). Despite gained insights on the structure of S100B, it remains unclear how its calcium and zinc binding properties regulate its function on cellular level. Here we report a novel role of S100B in trace metal homeostasis, in particular the regulation of zinc levels in the brain. Our results show that S100B at increased extracellular levels is not toxic, persists at high levels, and is taken up into neurons, as shown by cell culture and biochemical analysis. Combining protein bioimaging and zinc quantitation, along with a zinc-binding impaired S100B variant, we conclude that S100B effectively scavenges zinc ions through specific binding, resulting in a redistribution of the intracellular zinc pool. Our results indicate that scavenging of zinc by increased levels of S100B affects calcium levels in vitro. Thereby S100B is able to mediate the cross talk between calcium and zinc homeostasis. Further, we investigated a possible new neuro-protective role of S100B in excitotoxicity via its effects on calcium and zinc homeostasis. Exposure of cells to zinc-S100B but not the zinc-binding impaired S100B results in an inhibition of excitotoxicity. We conclude that in addition to its known functions, S100B acts as sensor and regulator of elevated zinc levels in the brain and this metal-buffering activity is tied to a neuroprotective role.

The Zn2+ and Ca2+‐binding S100B and S100A1 proteins: beyond the myths

“…S100B has long been considered a Zn 2+ ‐binding protein (Baudier et al ., ) and, as such, may function as a Zn 2+ ‐buffering protein able to mediate cross talk between zinc and calcium homeostasis (Hagmeyer et al ., ). By using coordinating residues on both protomers, zinc ions bridge the dimeric structure of S100B (Ostendorp et al ., ), increase the Ca 2+ affinity of S100B and promote the Ca 2+ ‐dependent interactions of S100B dimers with target proteins (Yu & Fraser, ; Gilquin et al ., ).…”

Hippocampal and Cerebellar Changes in Acute Restraint Stress and the Impact of Pretreatment with Ceftriaxone

“…S100B also regulates the intracellular level of free calcium in neurons and astrocytes. S100B buffers zinc in the brain, and this is linked to a neuroprotective function through indirect effects on calcium levels and inhibition of excitotoxicity [56].…”

The Role of Trace Metals in Alzheimer’s Disease

“…Inflammation, protein misfolding, and aggregation, as well as neurodegeneration, lead to increased levels of so-called alarmins or DAMPs that include several cytokines including those from the S100 family. The S100 proteins are engaged in classical calcium-activated signaling but recent work has shown their involvement in new biochemical mechanisms in the brain related to the prevention of protein aggregation (113) and sensing of neuronal Ca and Zn levels (114). Therefore, S100 alarmins are implicated in the maintenance of protein homeostasis (proteostasis) and metal ion homeostasis (metallostasis) in the brain.…”