4CO8: Structure Of The Dna Binding Ets Domain Of Human Etv4

Citation:
Abstract
Ets transcription factors, which share the conserved Ets DNA-binding domain, number nearly 30 members in humans and are particularly involved in developmental processes. Their deregulation following changes in expression, transcriptional activity, or by chromosomal translocation plays a critical role in carcinogenesis. Ets DNA binding, selectivity, and regulation have been extensively studied; however, questions still arise regarding binding specificity outside the core GGA recognition sequence and the mode of action of Ets post-translational modifications. Here, we report the crystal structures of Etv1, Etv4, Etv5, and Fev, alone and in complex with DNA. We identify previously unrecognized features of the protein-DNA interface. Interactions with the DNA backbone account for most of the binding affinity. We describe a highly coordinated network of water molecules acting in base selection upstream of the GGAA core and the structural features that may account for discrimination against methylated cytidine residues. Unexpectedly, all proteins crystallized as disulfide-linked dimers, exhibiting a novel interface (distant to the DNA recognition helix). Homodimers of Etv1, Etv4, and Etv5 could be reduced to monomers, leading to a 40-200-fold increase in DNA binding affinity. Hence, we present the first indication of a redox-dependent regulatory mechanism that may control the activity of this subset of oncogenic Ets transcription factors.
PDB ID: 4CO8Download
MMDB ID: 117202
PDB Deposition Date: 2014/1/27
Updated in MMDB: 2015/06
Experimental Method:
x-ray diffraction
Resolution: 1.05  Å
Source Organism:
Similar Structures:
Biological Unit for 4CO8: dimeric; determined by author and by software (PISA)
Molecular Components in 4CO8
Label Count Molecule
Proteins (2 molecules)
2
ETS Translocation Variant 4(Gene symbol: ETV4)
Molecule annotation
Chemicals (6 molecules)
1
6
* Click molecule labels to explore molecular sequence information.

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