Solution structure and dynamics of human metallothionein-3 (MT-3)

Abstract

Alzheimer’s disease is characterized by progressive loss of neurons accompanied by the formation of intraneural neurofibrillary tangles and extracellular amyloid plaques. Human neuronal growth inhibitory factor, classified as metallothionein-3 (MT-3), was found to be related to the neurotrophic activity promoting cortical neuron survival and dendrite outgrowth in the cell culture studies. We have determined the solution structure of the α-domain of human MT-3 (residues 32–68) by multinuclear and multidimensional NMR spectroscopy in combination with the molecular dynamic simulated annealing approach. The human MT-3 shows two metal–thiolate clusters, one in the N-terminus (β-domain) and one in the C-terminus (α-domain). The overall fold of the α-domain is similar to that of mouse MT-3. However, human MT-3 has a longer loop in the acidic hexapeptide insertion than that of mouse MT-3. Surprisingly, the backbone dynamics of the protein revealed that the β-domain exhibits similar internal motion to the α-domain, although the N-terminal residues are more flexible. Our results may provide useful information for understanding the structure–function relationship of human MT-3.