Functional Domains Of The Ets Transcription Factors

The ETS genes encode sequence-specific DNA-binding proteins and function as transcription factors [3-7]. ETS proteins bind as monomers (with the exception of GAB Pee) to the-GGAA/T-core motif present in the transcriptional regulatory regions of many cellular, viral promoters and enhancers [5,6]. Comparison of DNA-binding sequences determined by the site selection methods, as well as binding of ETS proteins to different target genes, reveals that the sequence surrounding the—GGAA/T-core strongly influences the binding of ETS family proteins [3, 57], Transcriptional control of unique ETS target genes depends on the specific ETS protein(s) expressed in a given cell type and its ability to bind the target sequence.

3.1. DNA-Binding Domain

The secondary structure of the ETS DNA binding domains of human FLI1 and mouse ETS1 proteins has been determined by NMR analyses [3, 5-6], These studies predict the existence of three alpha helices and a 4-stranded /6-sheet, similar to structures of the winged helix-turn-helix family of DNA-binding proteins. X-ray crystallographic analysis of ETS proteins in the presence or the absence of DNA provides data further supporting this structural model. The amino acids capable of forming this structure, as well as amino acids involved in the interaction with the DNA, as expected, are also highly conserved. This could be one of the reasons why different ETS proteins recognize the—GGAA/T—core sequence.

3.2. Transactivation Domain

The transactivation domains are located outside of the ETS DNA-binding domain. Interestingly, these transactivation regions map to weakly homologous or divergent (A, B and R) regions of the ETS proteins. The presence of a transactivation domain located in a divergent region provides greater flexibility and an opportunity to interact differently and uniquely with other proteins in order to increase their capacity to modulate the activities of a large number of target genes. The ETS proteins interact with other proteins in the presence or absence of DNA. Such interaction increases the stability and affinities for ETS-binding sequences. The protein-protein interaction domain in some of the ETS proteins is both flexible and distinct and is located in different regions of ETS proteins. Protein-protein interactions are able to direct specific ETS proteins to act on promoters or enhancers that contain multiple transcription factor binding sites; this type of interaction increases their potential to activate different target genes. It should be noted that while most family members function as activators of transcription, some function as repressors (e.g., ERP).

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