In a number of yeast two-hybrid screens, we have found clones that contained parts of the human metallothionein 2A (MT2A) nucleotide sequence. All of these clones were out-of-frame relative to the MT2A coding sequence and activated the yeast reporters in the presence of the Gal4 DNA binding domain but irrespective of the bait protein. Reporter gene activation was abolished when activation domain and MT2A coding sequences were brought in-frame. In light of these findings, we evaluated all recently reported interactions with metallothioneins because our out-of-frame proline-rich protein might have been the actual interaction partner in some of these studies.