1. Structured and disordered regions cooperatively mediate DNA-binding autoinhibition of ETS factors ETV1, ETV4 and ETV5
- Author
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Mark Okon, Barbara J. Graves, Jedediah J Doane, Frank G. Whitby, Simon L. Currie, Desmond K. W. Lau, and Lawrence P. McIntosh
- Subjects
Protein Conformation, alpha-Helical ,0301 basic medicine ,NAR Breakthrough Article ,Gene Expression ,Plasma protein binding ,Biology ,Crystallography, X-Ray ,DNA-binding protein ,ETV1 ,03 medical and health sciences ,chemistry.chemical_compound ,Protein structure ,Proto-Oncogene Proteins ,Escherichia coli ,Genetics ,Protein Interaction Domains and Motifs ,Cloning, Molecular ,Binding site ,Transcription factor ,Binding Sites ,Proto-Oncogene Proteins c-ets ,030102 biochemistry & molecular biology ,Lysine ,Acetylation ,DNA ,Recombinant Proteins ,Cell biology ,DNA-Binding Proteins ,Intrinsically Disordered Proteins ,Kinetics ,030104 developmental biology ,chemistry ,Adenovirus E1A Proteins ,Signal transduction ,Protein Processing, Post-Translational ,Protein Binding ,Transcription Factors - Abstract
Autoinhibition enables spatial and temporal regulation of cellular processes by coupling protein activity to surrounding conditions, often via protein partnerships or signaling pathways. We report the molecular basis of DNA-binding autoinhibition of ETS transcription factors ETV1, ETV4 and ETV5, which are often overexpressed in prostate cancer. Inhibitory elements that cooperate to repress DNA binding were identified in regions N- and C-terminal of the ETS domain. Crystal structures of these three factors revealed an α-helix in the C-terminal inhibitory domain that packs against the ETS domain and perturbs the conformation of its DNA-recognition helix. Nuclear magnetic resonance spectroscopy demonstrated that the N-terminal inhibitory domain (NID) is intrinsically disordered, yet utilizes transient intramolecular interactions with the DNA-recognition helix of the ETS domain to mediate autoinhibition. Acetylation of selected lysines within the NID activates DNA binding. This investigation revealed a distinctive mechanism for DNA-binding autoinhibition in the ETV1/4/5 subfamily involving a network of intramolecular interactions not present in other ETS factors. These distinguishing inhibitory elements provide a platform through which cellular triggers, such as protein–protein interactions or post-translational modifications, may specifically regulate the function of these oncogenic proteins.
- Published
- 2017