title: Bioactivity of metallothionein-3 correlates with its novel beta domain sequence rather than metal binding properties.
abstract: Human and mouse metallothionein-3 (MT-3) molecules exhibit the same metal binding stoichiometry with Zn(II), Cd(II), or Cu(I) as MT-1 or MT-2 molecules, suggesting that MT-3 consists of two domains enfolding separate polymetallic clusters. The kinetic reactivities of Zn(II) complexes of MT-3 with the chelator ethylenediaminetetraacetic acid (EDTA) or the thiol reagent dithiobis(2-nitrobenzoic acid) (DTNB) resembles the reactivity of ZnMT-1. Furthermore, the candidate alpha and beta domain peptides of human MT-3 are very similar to MT-1 domain peptides in the reactivity of Zn(II) complexes. Zn(II) complexes of human and mouse MT-3 inhibit the survival of rat cortical neurons cultured in the presence of an Alzheimer's disease brain extract. Inhibitory activity is unique to the MT-3 isoform and is a property of the N-terminal beta domain. The inhibitory activity of the 32-residue MT-3 beta domain is abolished by a double mutation within the beta domain resulting in the conversion of the C-P-C-P sequence to either C-S-C-A or C-T-C-T. Thus, the bioactivity arises from a novel structure of the N-terminal beta domain of MT-3 and not any unusual metal-binding properties.
authors.affiliation: Department of Medicine, University of Utah Health Science Center, Salt Lake City 84132, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Sewell
authors.forename: L T
authors.initials: LT
authors.lastname: Jensen
authors.forename: J C
authors.initials: JC
authors.lastname: Erickson
authors.forename: R D
authors.initials: RD
authors.lastname: Palmiter
authors.forename: D R
authors.initials: DR
authors.lastname: Winge
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D006801:Humans; D008668:Metallothionein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000090023:Metallothionein 3; D008670:Metals / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
chemical_list: D000090023:Metallothionein 3; D008670:Metals; C000715430:Mt3 protein, mouse; D011994:Recombinant Proteins; D008668:Metallothionein