Abstract
Ets-2, like its closely related homologue Ets-1, is a member of the Ets family of DNA binding transcription factors. Both proteins are subject to multiple levels of regulation of their DNA binding and transactivation properties. One such regulatory mechanism is the presence of an autoinhibitory module, which in Ets-1 allosterically inhibits the DNA binding activity. This inhibition can be relieved by interaction with protein partners or cooperative binding to closely separated Ets binding sites in a palindromic arrangement. In this study we describe the 2.5 Å resolution crystal structure of a DNA complex of the Ets-2 Ets domain. The Ets domain crystallized with two distinct species in the asymmetric unit, which closely resemble the autoinhibited and DNA bound forms of Ets-1. This discovery prompted us to re-evaluate the current model for the autoinhibitory mechanism and the structural basis for cooperative DNA binding. In contrast to Ets-1, in which the autoinhibition is caused by a combination of allosteric and steric mechanisms, we were unable to find clear evidence for the allosteric mechanism in Ets-2. We also demonstrated two possibly distinct types of cooperative binding to substrates with Ets binding motifs separated by four and six base pairs and suggest possible molecular mechanisms for this behavior.
Highlights
ETS transcription factors regulate expression of genes involved in development and cancer
Another mechanism of regulation that is shared by both Ets-1 and Ets-2 is the phenomenon of cooperative binding to palindromic repeats of the Ets binding site (EBS) (16 –18), which is not generally observed in the wider Ets family proteins, which typically bind single EBS motifs with high affinity
Previous structural studies of the closely related Ets-1 established a model for autoinhibition in which the unfolding of HI-1 upon binding DNA reduces the affinity of the autoinhibited form
Summary
ETS transcription factors regulate expression of genes involved in development and cancer. A recent study established a possible mechanism by which this inhibition proceeds, finding that the phosphorylated serine-rich region is intrinsically disordered and forms dynamic interactions with the core Ets domain, including regions of the DNA recognition interface [15] Another mechanism of regulation that is shared by both Ets-1 and Ets-2 is the phenomenon of cooperative binding to palindromic repeats of the Ets binding site (EBS) (16 –18), which is not generally observed in the wider Ets family proteins, which typically bind single EBS motifs with high affinity. The association and interfaces formed between molecules in the asymmetric units give insights into novel aspects of the autoinhibitory mechanism and cooperative binding
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