ETV6 (or TEL), a transcriptional repressor belonging to the ETS family, is frequently involved in chromosomal translocations linked with human cancers. It displays a DNA-binding mode distinct from other ETS proteins due to the presence of a self-associating PNT domain. In this study, we used NMR spectroscopy to dissect the structural and dynamic bases for the autoinhibition of ETV6 DNA binding by sequences C-terminal to its ETS domain. The C-terminal inhibitory domain (CID) contains two helices, H4 and H5, which sterically block the DNA-binding interface of the ETS domain. Importantly, these appended helices are only marginally stable as revealed by amide hydrogen exchange and (15)N relaxation measurements. The CID is thus poised to undergo a facile conformational change as required for DNA binding. The CID also dampens millisecond timescale motions of the ETS domain hypothesized to be critical for the recognition of specific ETS target sequences. This work illustrates the use of appended sequences on conserved structural domains to generate biological diversity and complements previous studies of the allosteric mechanism of ETS1 autoinhibition to reveal both common and divergent features underlying the regulation of DNA binding by ETS transcription factors.
ETV6 (or n class="Gene">TEL), a transcriptional repressor belonging to the ETS family, is frequently involved in chromosomal translocations linked with humancancers. It displays a DNA-binding mode distinct from other ETS proteins due to the presence of a self-associating PNT domain. In this study, we used NMR spectroscopy to dissect the structural and dynamic bases for the autoinhibition of ETV6 DNA binding by sequences C-terminal to its ETS domain. The C-terminal inhibitory domain (CID) contains two helices, H4 and H5, which sterically block the DNA-binding interface of the ETS domain. Importantly, these appended helices are only marginally stable as revealed by amidehydrogen exchange and (15)N relaxation measurements. The CID is thus poised to undergo a facile conformational change as required for DNA binding. The CID also dampens millisecond timescale motions of the ETS domain hypothesized to be critical for the recognition of specific ETS target sequences. This work illustrates the use of appended sequences on conserved structural domains to generate biological diversity and complements previous studies of the allosteric mechanism of ETS1 autoinhibition to reveal both common and divergent features underlying the regulation of DNA binding by ETS transcription factors.
Authors: Wolfgang Rieping; Michael Habeck; Benjamin Bardiaux; Aymeric Bernard; Thérèse E Malliavin; Michael Nilges Journal: Bioinformatics Date: 2006-11-22 Impact factor: 6.937
Authors: Gregory M Lee; Miles A Pufall; Charles A Meeker; Hyun-Seo Kang; Barbara J Graves; Lawrence P McIntosh Journal: J Mol Biol Date: 2008-07-29 Impact factor: 5.469
Authors: Daniel Fitzsimmons; Kara Lukin; Ryan Lutz; Colin W Garvie; Cynthia Wolberger; James Hagman Journal: J Mol Biol Date: 2009-07-17 Impact factor: 5.469
Authors: M Guy Roukens; Mariam Alloul-Ramdhani; Alfred C O Vertegaal; Zeinab Anvarian; Crina I A Balog; André M Deelder; Paul J Hensbergen; David A Baker Journal: Mol Cell Biol Date: 2008-01-22 Impact factor: 4.272
Authors: Michael Y Zhang; Jane E Churpek; Siobán B Keel; Tom Walsh; Ming K Lee; Keith R Loeb; Suleyman Gulsuner; Colin C Pritchard; Marilyn Sanchez-Bonilla; Jeffrey J Delrow; Ryan S Basom; Melissa Forouhar; Boglarka Gyurkocza; Bradford S Schwartz; Barbara Neistadt; Rafael Marquez; Christopher J Mariani; Scott A Coats; Inga Hofmann; R Coleman Lindsley; David A Williams; Janis L Abkowitz; Marshall S Horwitz; Mary-Claire King; Lucy A Godley; Akiko Shimamura Journal: Nat Genet Date: 2015-01-12 Impact factor: 38.330
Authors: Soumya De; Anson C K Chan; H Jerome Coyne; Niraja Bhachech; Ulrike Hermsdorf; Mark Okon; Michael E P Murphy; Barbara J Graves; Lawrence P McIntosh Journal: J Mol Biol Date: 2013-12-12 Impact factor: 5.469