Abstract
The transcription factor Gli3 is acting mainly as a transcriptional repressor in the Sonic hedgehog signal transduction pathway. Gli3 contains a repressor domain in its N-terminus from residue G106 to E236. In this study we have characterized the intracellular structure of the Gli3 repressor domain using a combined bioinformatics and experimental approach. According to our findings the Gli3 repressor domain while being intrinsically disordered contains predicted anchor sites for partner interactions. The obvious interaction partners to test were Ski and DNA; however, with both of these the structure of Gli3 repressor domain remained disordered. To locate residues important for the repressor function we mutated several residues within the Gli3 repressor domain. Two of these, H141A and H157N, targeting predicted helical regions, significantly decreased transcriptional repression and thus identify important functional parts of the domain.
Highlights
The expression of human genes is controlled by numerous transcription factors
The second one is histone deacetylase independent, involving the domain that we previously identified and named the repressor domain (RD) [7]
In regard to its function as a transcriptional repressor we aimed to investigate whether Gli3RD binds Ski or DNA
Summary
The expression of human genes is controlled by numerous transcription factors. Depending on the physiological context genes are activated by transcriptional activators or repressed by transcriptional repressors. There are three transcription factors (Gli, Gli and Gli3) in the Sonic hedgehog signal transduction pathway [1]. In their central part these proteins contain a conserved DNA binding domain (DBD) consisting of five zinc-fingers. The first one, common to all three Gli proteins, is dependent on Sufu and histone deacetylase [6]. The second one is histone deacetylase independent, involving the domain that we previously identified and named the repressor domain (RD) [7]. Third mechanism of negative transcriptional regulation by Gli has been suggested to involve Ski and histone deacetylation, indicating a general mechanism for all Gli proteins [8]. Gli transcriptional repression has been shown in Sufu knockout mice, suggesting Sufu independent repression mechanism [9]
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