Evidence for non-isostructural replacement of Zn(2+) with Cd(2+) in the beta-domain of brain-specific metallothionein-3.

Metallothionein-3 (MT-3) is a brain-specific MT, which is downregulated in Alzheimer's disease. The N-terminal region of CdMT-3 is highly dynamic and has escaped structural characterization by nuclear magnetic resonance. We have used electrospray ionization mass spectrometry to probe conformational states of cadmium- and zinc-substituted metalloforms of MT-3 and can demonstrate that the N-terminal beta-domain of MT-3 filled with Cd(2+) has a more open conformation than that filled with Zn(2+). The results suggest that the larger Cd(2+) ions cannot isostructurally replace zinc in the beta-domain of MT-3 whereas in the case of MT-1 and MT-2 the replacement is isostructural. Specific metal binding properties of the beta-domain of MT-3 may be essential for fulfilling the specific role of MT-3 in the brain.