Abstract
The Ets family of eukaryotic transcription factors is based around the conserved Ets DNA-binding domain. Although their DNA-binding selectivity is biochemically and structurally well characterized, structures of homodimeric and ternary complexes point to Ets domains functioning as versatile protein-interaction modules. In the present paper, we review the progress made over the last decade to elucidate the structural mechanisms involved in modulation of DNA binding and protein partner selection during dimerization. We see that Ets domains, although conserved around a core architecture, have evolved to utilize a variety of interaction surfaces and binding mechanisms, reflecting Ets domains as dynamic interfaces for both DNA and protein interaction. Furthermore, we discuss recent advances in drug development for inhibition of Ets factors, and the roles structural biology can play in their future.
Highlights
The Ets TF family is found throughout the metazoa, comprising 28 members in humans [1,2], all containing the evolutionarily conserved DNA-binding Ets domain which binds the invariant DNA sequence 5 GGA(A/T)-3 [2]
Ets proteins are subclassified by the presence of further domains associated with PPIs or transcriptional regulation [2,3], including the TCF and PEA3 subfamilies
PNT domains are frequently found N-terminal to the Ets domain, involved in PPI and homodimerization [8,9] (Figure 1A)
Summary
The Ets TF (transcription factor) family is found throughout the metazoa, comprising 28 members in humans [1,2], all containing the evolutionarily conserved DNA-binding Ets domain which binds the invariant DNA sequence 5 GGA(A/T)-3 [2]. These structures have shed light on some mechanisms used to regulate Ets function, interaction interfaces utilized in binding cooperativity and sequence selectivity of Ets ternary complexes on tandem DNA motifs [10,11,12]. Ets domain structures have helped to elucidate mechanisms of autoinhibition of DNA binding compared with co-operative binding [13,14,15] Such structural studies have demonstrated the evolution of multiple independent PPI interfaces on Ets domains, thereby illustrating their versatile nature, responsible for binding DNA, and critical for the regulation of DNA binding and transcriptional activity. Ets overexpression may follow chromosome rearrangements, from copy gains of ETV1 in melanoma [23], to fusion of ERG or ETV1
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