ArticleProceedings of the National Academy of Sciences of the United States of America2007
Multiple aromatic side chains within a disordered structure are critical for transcription and transforming activity of EWS family oncoproteins.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 104 citations in OpenAlex.
- Heterogeneous Folding Intermediates Govern the Conformational Pathway of the RNA Recognition Motif Domain of the Ewing Sarcoma Protein.Biomolecules · 2025Article
- Molecular basis of EWS interdomain self-association and its role in condensate formation.Protein science : a publication of the Protein Society · 2025Article
- Subversion of mRNA degradation pathways by EWSR1::FLI1 represents a therapeutic vulnerability in Ewing sarcoma.Nature communications · 2025Article
- Phase separation of the oncogenic fusion protein EWS::FLI1 is modulated by its DNA-binding domain.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Hijacking the BAF complex: the mechanistic interplay of ARID1A and EWS::FLI1 in Ewing sarcoma.Molecular oncology · 2025Article
- Review
- SHARK enables sensitive detection of evolutionary homologs and functional analogs in unalignable and disordered sequences.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Insights into Molecular Diversity within the FUS/EWS/TAF15 Protein Family: Unraveling Phase Separation of the N-Terminal Low-Complexity Domain from RNA-Binding Protein EWS.Journal of the American Chemical Society · 2024Article
- Insights into Molecular Diversity within the FET Family: Unraveling Phase Separation of the N-Terminal Low Complexity Domain from RNA-Binding Protein EWS.bioRxiv : the preprint server for biology · 2023Article
- Intrinsically disordered proteins and proteins with intrinsically disordered regions in neurodegenerative diseases.Biophysical reviews · 2022Review
- Salt-Inducible Kinase 1 is a potential therapeutic target in Desmoplastic Small Round Cell Tumor.Oncogenesis · 2022Article
- Article
- Targeting EYA3 in Ewing Sarcoma Retards Tumor Growth and Angiogenesis.Molecular cancer therapeutics · 2021Article
- Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis.Journal of visualized experiments : JoVE · 2020Article
- Targeting intrinsically disordered proteins involved in cancer.Cellular and molecular life sciences : CMLS · 2020Review
- Article
- Article
- Transcriptomic analysis functionally maps the intrinsically disordered domain of EWS/FLI and reveals novel transcriptional dependencies for oncogenesis.Genes & cancer · 2019Article
- Article
- Differential interaction of PRMT1 with RGG-boxes of the FET family proteins EWS and TAF15.Protein science : a publication of the Protein Society · 2018Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 3 countries.
Funding
Abstract
Chromosomal translocations involving the N-terminal approximately 250 residues of the Ewings sarcoma (EWS) oncogene produce a group of EWS fusion proteins (EFPs) that cause several distinct human cancers. EFPs are potent transcriptional activators and interact with other proteins required for mRNA biogenesis, indicating that EFPs induce tumorigenesis by perturbing gene expression. Although EFPs were discovered more than a decade ago, molecular analysis has been greatly hindered by the repetitive EWS activation domain (EAD) structure, containing multiple degenerate hexapeptide repeats (consensus SYGQQS) with a conserved tyrosine residue. By exploiting total gene synthesis, we have been able to systematically mutagenize the EAD and determine the effect on transcriptional activation by EWS/ATF1 and cellular transformation by EWS/Fli1. In both assays, we find the following requirements for EAD function. First, multiple tyrosine residues are essential. Second, phenylalanine can effectively substitute for tyrosine, showing that an aromatic ring can confer EAD function in the absence of tyrosine phosphorylation. Third, there is little requirement for specific peptide sequences and, thus, overall sequence composition (and not the degenerate hexapeptide repeat) confers EAD activity. Consistent with the above findings, we also report that the EAD is intrinsically disordered. However, a sensitive computational predictor of natural protein disorder (PONDR VL3) identifies potential molecular recognition features that are tyrosine-dependent and that correlate well with EAD function. In summary we have uncovered several molecular features of the EAD that will impact future studies of the broader EFP family and molecular recognition by complex intrinsically disordered proteins.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.