The fact that dimeric forms of ZnT3 were resistant to reducing agents and increased in response to oxidative stress, lead us to investigate tyrosine-mediated dimerization. Since its discovery in 1959, dityrosine formation has been described as a post-translational modification related with cellular stress and disease. Dityrosine modifications are produced in response to oxidative stress, aging, UV and c irradiation. Increased levels of dityrosine have been found in atheromatous plates, cataracts, acute inflammation, systemic bacterial infection and recently associated with a-synuclein fibrillogenesis and Ab amyloid oligomerization. Di-tyrosine formation as a normal post-translational modification has been described only in a limited group of structural proteins of the bacteria cell wall and insect ligaments,LY2157299 and in proteins of the extracellular matrix as collagen and elastin. Here we show tyrosine dimerization in a polytopic transmembrane protein, mediated by tyrosine residues in the carboxy terminal domain. In contrast to the described damage connotation and structural roles of dityrosine bonds, ZnT3 tyrosine modification presents a new functional paradigm for dityrosine bonds as regulators of both subcellular localization and metal transport activity. This ZnT3 post-translational modification occurs spontaneously and it is regulated by oxidative stress. Interestingly,LY294002 the gain-of-function phenotype obtained by mutagenesis of tyrosine 357 in human ZnT3 indicates that tyrosine 357 might regulate the availability or proximity of Y330 and Y372 for dimer formation. Tyrosine residues involved in dityrosine bond formation or those adjacent could be subject to tyrosine post-translational modifications that could modulate dimerization and function of membrane proteins. For example NetPhos 2.0 predicts that tyrosine 357 in human ZnT3, possesses a high probability for being a phosphate acceptor. Additionally, nitrosylation of tyrosines, a mofidication induced by oxidative stress, could modulate dityrosine bond formation of zinc transporters. These posttranslational events could affect tyrosine-dependent covalent dimerization, zinc transport, and cell response to metal challenges.