A SHORT, DISORDERED PROTEIN REGION MEDIATES INTERACTIONS BETWEEN THE HOMEODOMAIN OF THE YEAST ALPHA-2 PROTEIN AND THE MCM1 PROTEIN

Homeodomains are folded into a characteristic three-dimensional structure capable of recognizing DNA in a sequence-specific manner. We show that correct target site selection by the yeast alpha2 protein requires, as well as its homeodomain, an adjacent short and apparently unstructured region of the protein. This flexible homeodomain extension is responsible for specifying an interaction with a second regulatory protein, MCM1, which permits the cooperative binding of the two proteins to an operator. Two additional experiments suggest that this extension-homeodomain arrangement is likely to have some generality. First, when the extension of alpha2 is grafted onto the Drosophila engrailed homeodomain, it yields a protein with the DNA binding specificity of engrailed and the ability to bind cooperatively to DNA with MCM1. Second, the alpha2 extension specifies interaction not only with the yeast MCM1 protein, but also with the related human protein SRF.