5ILU

Autoinhibited ETV4

Summary for 5ILU

• Entry DOI: 10.2210/pdb5ilu/pdb
• Related: 5ILS 5ILV
• Descriptor: ETS translocation variant 4 (2 entities in total)
• Functional Keywords: etv4, ets, transcription factor, autoinhibition transcription, dna binding, dna binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 11449.16

Authors

Whitby, F.G.,Currie, S.L. (deposition date: 2016-03-04, release date: 2017-02-22, Last modification date: 2024-10-30)

Primary citation

Currie, S.L.,Lau, D.K.W.,Doane, J.J.,Whitby, F.G.,Okon, M.,McIntosh, L.P.,Graves, B.J.
Structured and disordered regions cooperatively mediate DNA-binding autoinhibition of ETS factors ETV1, ETV4 and ETV5.
Nucleic Acids Res., 45:2223-2241, 2017

PubMed 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.

PubMed: 28161714
DOI: 10.1093/nar/gkx068

Experimental method

X-RAY DIFFRACTION (1.101 Å)