Search:
Computing and Library Services - delivering an inspiring information environment

Structures of the Ets Protein DNA-binding Domains of Transcription Factors Etv1, Etv4, Etv5, and Fev: Determinants of DNA Binding and Redox Regulation by Disulfide Bond Formation.

Cooper, Christopher D.O., Newman, Joseph A., Aitkenhead, Hazel, Allerston, Charles K. and Gileadi, Opher (2015) Structures of the Ets Protein DNA-binding Domains of Transcription Factors Etv1, Etv4, Etv5, and Fev: Determinants of DNA Binding and Redox Regulation by Disulfide Bond Formation. The Journal of Biological Chemistry, 290 (22). pp. 13692-13709. ISSN 1083-351X

[img]
Preview
PDF - Published Version
Available under License Creative Commons Attribution.

Download (8MB) | Preview

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.

Item Type: Article
Additional Information: C.D.O.Cooper is first co-author/ equal contribution
Subjects: Q Science > QH Natural history > QH301 Biology
Schools: School of Applied Sciences
Depositing User: Christopher Cooper
Date Deposited: 23 Nov 2015 11:47
Last Modified: 12 Dec 2015 01:38
URI: http://eprints.hud.ac.uk/id/eprint/26490

Downloads

Downloads per month over past year

Repository Staff Only: item control page

View Item View Item

University of Huddersfield, Queensgate, Huddersfield, HD1 3DH Copyright and Disclaimer All rights reserved ©