Structural view on the role of WT1’s zinc finger 1 in DNA binding

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Abstract

Abstract The WT1 protein is a transcription factor that controls genes involved in cell proliferation, differentiation and apoptosis. It has become increasing apparent that WT1 can act both as a tumor suppressor and oncogene in a tissue specific manner. This opposing role of WT1 is linked to its underlying transcriptional regulatory function, which involves the specific binding to its regulatory elements on gene promoters. WT1 binds DNA using it C-terminal domain made up of 4 C2H2-typ zinc fingers. This same zinc finger domain is used to bind RNA and proteins and it is still not clear how each zinc finger contributes to this promiscuous binding behavior. The molecular details of DNA binding by zinc finger 2 to 4 have been described but it remains to be determined whether or not zinc finger 1 binds DNA and if so whether it exhibits any DNA binding specificity. We present the X-ray structures of zinc finger 1 to 3 bound to a 9 bp and an 8 bp DNA. The two structures refined to 1.7 Å, show no DNA binding specificity for zinc finger 1. The only DNA interactions involving zinc finger 1 are crystal-packing interactions with a symmetry related molecule. In the structure of zinc finger 1 to 3 bound to the 9 bp DNA we observe a shift in the DNA binding positions for zinc fingers 2 and 3. These structures provide molecular detail into the WT1-DNA interaction showing that zinc finger 1 only modestly contributes to DNA binding affinity through transient interactions. The dislocation of zinc finger 2 and 3 emphasizes the importance of zinc finger 4 for maintaining gene transcriptional specificity.

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