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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 CD, Newman JA, Aitkenhead H, Allerston CK, Gileadi O
J Biol Chem 290 13692-709 (2015)
Related entries: 2ypr, 3zp5, 4avp, 4bnc, 4co8, 4uno

Cited: 23 times
EuropePMC logo PMID: 25866208

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.

Articles - 4uuv mentioned but not cited (6)

  1. ETV4 and AP1 Transcription Factors Form Multivalent Interactions with three Sites on the MED25 Activator-Interacting Domain. Currie SL, Doane JJ, Evans KS, Bhachech N, Madison BJ, Lau DKW, McIntosh LP, Skalicky JJ, Clark KA, Graves BJ. J Mol Biol 429 2975-2995 (2017)
  2. 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 CD, Newman JA, Aitkenhead H, Allerston CK, Gileadi O. J Biol Chem 290 13692-13709 (2015)
  3. Transcriptomic profile of Pea3 family members reveal regulatory codes for axon outgrowth and neuronal connection specificity. Kandemir B, Gulfidan G, Arga KY, Yilmaz B, Kurnaz IA. Sci Rep 10 18162 (2020)
  4. Comparative structure analysis of the ETSi domain of ERG3 and its complex with the E74 promoter DNA sequence. Sharma R, Gangwar SP, Saxena AK. Acta Crystallogr F Struct Biol Commun 74 656-663 (2018)
  5. pyDockDNA: A new web server for energy-based protein-DNA docking and scoring. Rodríguez-Lumbreras LA, Jiménez-García B, Giménez-Santamarina S, Fernández-Recio J. Front Mol Biosci 9 988996 (2022)
  6. Comparative structure analysis of the ETSi domain of ERG3 and its complex with the E74 promoter DNA sequence. Corrigendum. Sharma R, Gangwar SP, Saxena AK. Acta Crystallogr F Struct Biol Commun 75 397-398 (2019)


Reviews citing this publication (3)

  1. Genetic-epigenetic interactions in cis: a major focus in the post-GWAS era. Do C, Shearer A, Suzuki M, Terry MB, Gelernter J, Greally JM, Tycko B. Genome Biol 18 120 (2017)
  2. Function and regulation of the PEA3 subfamily of ETS transcription factors in cancer. Qi T, Qu Q, Li G, Wang J, Zhu H, Yang Z, Sun Y, Lu Q, Qu J. Am J Cancer Res 10 3083-3105 (2020)
  3. Non-coding RNA-mediated epigenetic regulation of liver fibrosis. Yang JJ, Tao H, Deng ZY, Lu C, Li J. Metabolism 64 1386-1394 (2015)

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  1. Genome-wide quantification of the effects of DNA methylation on human gene regulation. Lea AJ, Vockley CM, Johnston RA, Del Carpio CA, Barreiro LB, Reddy TE, Tung J. Elife 7 e37513 (2018)
  2. Modulation of androgen receptor DNA binding activity through direct interaction with the ETS transcription factor ERG. Wasmuth EV, Hoover EA, Antar A, Klinge S, Chen Y, Sawyers CL. Proc Natl Acad Sci U S A 117 8584-8592 (2020)
  3. Differential sensitivity to methylated DNA by ETS-family transcription factors is intrinsically encoded in their DNA-binding domains. Stephens DC, Poon GM. Nucleic Acids Res 44 8671-8681 (2016)
  4. Structured and disordered regions cooperatively mediate DNA-binding autoinhibition of ETS factors ETV1, ETV4 and ETV5. Currie SL, Lau DKW, Doane JJ, Whitby FG, Okon M, McIntosh LP, Graves BJ. Nucleic Acids Res 45 2223-2241 (2017)
  5. HBx increases chromatin accessibility and ETV4 expression to regulate dishevelled-2 and promote HCC progression. Zheng C, Liu M, Ge Y, Qian Y, Fan H. Cell Death Dis 13 116 (2022)
  6. OX133, a monoclonal antibody recognizing protein-bound N-ethylmaleimide for the identification of reduced disulfide bonds in proteins. Holbrook LM, Kwong LS, Metcalfe CL, Fenouillet E, Jones IM, Barclay AN. MAbs 8 672-677 (2016)
  7. Genetic Study of Elf5 and Ehf in the Mouse Salivary Gland. Song EAC, Smalley K, Oyelakin A, Horeth E, Che M, Wrynn T, Osinski J, Romano RA, Sinha S. J Dent Res 102 340-348 (2023)
  8. Allosteric interference in oncogenic FLI1 and ERG transactions by mithramycins. Hou C, Mandal A, Rohr J, Tsodikov OV. Structure 29 404-412.e4 (2021)
  9. Context-dependent monoclonal antibodies against protein carbamidomethyl-cysteine. Cartee NMP, Lee SJ, Keep SG, Wang MM. PLoS One 15 e0242376 (2020)
  10. Dissolution of oncofusion transcription factor condensates for cancer therapy. Wang Y, Yu C, Pei G, Jia W, Li T, Li P. Nat Chem Biol 19 1223-1234 (2023)
  11. ETS variant transcription factor 5 and c-Myc cooperate in derepressing the human telomerase gene promoter via composite ETS/E-box motifs. Zhang F, Wang S, Zhu J. J Biol Chem 295 10062-10075 (2020)
  12. Molecular dynamics studies on the DNA-binding process of ERG. Beuerle MG, Dufton NP, Randi AM, Gould IR. Mol Biosyst 12 3600-3610 (2016)
  13. Structural Insight into the DNA Binding Function of Transcription Factor ERF. Hou C, McCown C, Ivanov DN, Tsodikov OV. Biochemistry (2020)
  14. Atrial natriuretic peptide signaling co-regulates lipid metabolism and ventricular conduction system gene expression in the embryonic heart. Mishra A, Tavasoli M, Sokolenko S, McMaster CR, Pasumarthi KBS. iScience 27 108748 (2024)


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