Structured and disordered regions cooperatively mediate DNA-binding autoinhibition of ETS factors ETV1, ETV4 and ETV5

Currie, Simon L.; Lau, Desmond; Doane, Jedediah J; Whitby, Frank G.; Okon, Mark; McIntosh, Lawrence P.; Graves, Barbara J.

doi:10.1093/nar/gkx068

Cited by 33 publications

(45 citation statements)

References 68 publications

(112 reference statements)

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“…4b). This matches the two-fold magnitude of DNA-binding autoinhibition that was previously attributed to H4 [57]. Mutation of the MED25-interaction site on H4 (Phe428Ala/Phe428Ala) or of the ETS domain-interaction site on H4 (Leu430Ala) both abrogated the activation of DNA binding by MED25 (Fig.…”

Section: Resultssupporting

confidence: 87%

“…We compared the 15 N-HSQC spectra for 15 N-labeled ETV4 DBD [57] with or without unlabeled MED25 ACID (Fig. S4a).…”

Section: Resultsmentioning

confidence: 99%

“…We previously demonstrated that α-helix H4 inhibits the DNA binding of the ETS domain of ETV4 [57]. Leu430 on the interior face of H4 is critical for this autoinhibition and interacts with conserved hydrophobic residues of the ETS domain.…”

Section: Resultsmentioning

confidence: 99%

“…Part of this specificity can be ascribed to the diverse flanking inhibitory regions that are specific to individual subfamilies of ETS factors. In the ETS1 and ETV1/4/5 subfamilies, both inhibitory α-helices that pack against the ETS domain and intrinsically disordered sequences contribute to autoinhibition [57, 67]. The subfamily-specific α-helices also provide unique scaffolds for intermolecular interactions.…”

Section: Discussionmentioning

confidence: 99%

“…MED25 interaction with H4 relieves autoinhibition from H4 but does not appear to disturb inhibition from the disordered N-terminal inhibitory domain. Interestingly, acetylation of lysines relieves the inhibition from this disordered domain [57]. MED25 also interacts with CBP, a protein acetyltransferase [53].…”

Section: Discussionmentioning

confidence: 99%

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ETV4 and AP1 Transcription Factors Form Multivalent Interactions with three Sites on the MED25 Activator-Interacting Domain

Currie

Doane

Evans

et al. 2017

Journal of Molecular Biology

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The recruitment of transcriptional cofactors by sequence-specific transcription factors challenges the basis of high affinity and selective interactions. Extending previous studies that the N-terminal activation domain (AD) of ETV5 interacts with Mediator subunit 25 (MED25), we establish that similar, aromatic-rich motifs located both in the AD and in the DNA-binding domain (DBD) of the related ETS factor ETV4 interact with MED25. These ETV4 regions bind MED25 independently, display distinct kinetics, and combine to contribute to a high-affinity interaction of full-length ETV4 with MED25. High-affinity interactions with MED25 are specific for the ETV1/4/5 subfamily as other ETS factors display weaker binding. The AD binds to a single site on MED25 and the DBD interacts with three MED25 sites, allowing for simultaneous binding of both domains in full-length ETV4. MED25 also stimulates the in vitro DNA binding activity of ETV4 by relieving autoinhibition. ETV1/4/5 factors are often overexpressed in prostate cancer and genome-wide studies in a prostate cancer cell line indicate that ETV4 and MED25 occupy enhancers that are enriched for ETS-binding sequences and are both functionally important for the transcription of genes regulated by these enhancers. AP1-motifs, which bind JUN and FOS transcription factor families, were observed in MED25-occupied regions and JUN/FOS also contact MED25; FOS strongly binds to the same MED25 site as ETV4 AD and JUN interacts with the other two MED25 sites. In summary, we describe features of the multivalent ETV4- and AP1-MED25 interactions, thereby implicating these factors in the recruitment of MED25 to transcriptional control elements.

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Section: Resultssupporting

confidence: 87%

“…We compared the 15 N-HSQC spectra for 15 N-labeled ETV4 DBD [57] with or without unlabeled MED25 ACID (Fig. S4a).…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

ETV4 and AP1 Transcription Factors Form Multivalent Interactions with three Sites on the MED25 Activator-Interacting Domain

Currie

Doane

Evans

et al. 2017

Journal of Molecular Biology

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Genetic Code Expansion Tools to Study Lysine Acylation

Neumann‐Staubitz¹,

Lammers

Neumann³

2021

Advanced Biology

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Lysine acylation is a ubiquitous protein modification that controls various aspects of protein function, such as the activity, localization, and stability of enzymes. Mass spectrometric identification of lysine acylations has witnessed tremendous improvements in sensitivity over the last decade, facilitating the discovery of thousands of lysine acylation sites in proteins involved in all essential cellular functions across organisms of all domains of life. However, the vast majority of currently known acylation sites are of unknown function. Semi‐synthetic methods for installing lysine derivatives are ideally suited for in vitro experiments, while genetic code expansion (GCE) allows the installation and study of such lysine modifications, especially their dynamic properties, in vivo. An overview of the current state of the art is provided, and its potential is illustrated with case studies from recent literature. These include the application of engineered enzymes and GCE to install lysine modifications or photoactivatable crosslinker amino acids. Their use in the context of central metabolism, bacterial and viral pathogenicity, the cytoskeleton and chromatin dynamics, is investigated.

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Co‐translational Installation of Posttranslational Modifications by Non‐canonical Amino Acid Mutagenesis

Niu

Guo

2023

ChemBioChem

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Protein posttranslational modifications (PTMs) play critical roles in regulating cellular activities. Here we provide a survey of genetic code expansion (GCE) methods that were applied in the co‐translational installation and studies of PTMs through noncanonical amino acid (ncAA) mutagenesis. We begin by reviewing types of PTM that have been installed by GCE with a focus on modifications of tyrosine, serine, threonine, lysine, and arginine residues. We also discuss examples of applying these methods in biological studies. Finally, we end the piece with a short discussion on the challenges and the opportunities of the field.

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Structured and disordered regions cooperatively mediate DNA-binding autoinhibition of ETS factors ETV1, ETV4 and ETV5

Cited by 33 publications

References 68 publications

ETV4 and AP1 Transcription Factors Form Multivalent Interactions with three Sites on the MED25 Activator-Interacting Domain

ETV4 and AP1 Transcription Factors Form Multivalent Interactions with three Sites on the MED25 Activator-Interacting Domain

Genetic Code Expansion Tools to Study Lysine Acylation

Co‐translational Installation of Posttranslational Modifications by Non‐canonical Amino Acid Mutagenesis

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