ArticleProceedings of the National Academy of Sciences of the United States of America2017
Control of transcriptional activity by design of charge patterning in the intrinsically disordered RAM region of the Notch receptor.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 84 papers.
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Who cites it
84 citing papers in PubMed, 139 citations in OpenAlex.
- FAIDR-Desi: interactive software for feature analysis and design of intrinsically disordered regions.Bioinformatics (Oxford, England) · 2026Article
- Molecular dynamics simulations of intrinsically disordered protein regions enable biophysical interpretation of variant-effect predictors.HGG advances · 2026Article
- A composition-matching algorithm, MatchIDR, identifies prion-like domains that localize to stress granules.Protein science : a publication of the Protein Society · 2026Article
- The dynamic and heterogeneous composition of biomolecular condensates and its functional relevance.Nature reviews. Molecular cell biology · 2026Review
- Positive Selection Targeted Primate Genes that Encode Transposable Element Repressors.Genome biology and evolution · 2026Article
- Disordered but rhythmic-the role of intrinsic protein disorder in eukaryotic circadian timing.FEBS letters · 2026Review
- Molecular grammars of predicted intrinsically disordered regions that span the human proteome.Cell · 2026Article
- Statistical Physics-Based Approaches to Model the Function and Complexation of Disordered Proteins.The journal of physical chemistry. B · 2025Article
- Second-order allosteric control as a mechanism for compensatory mutations in B-cell translocation gene 2.Protein science : a publication of the Protein Society · 2025Article
- Bivalent interaction through an intrinsically disordered linker promotes transcription activation complex assembly in Notch signaling.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Noncovalent Lasso Entanglements are Common in Experimentally Derived Intrinsically Disordered Protein Ensembles and Strongly Influenced by Protein Length and Charge.The journal of physical chemistry. B · 2025Article
- MEDOC: A Fast, Scalable, and Mathematically Exact Algorithm for the Site-Specific Prediction of the Protonation Degree in Large Disordered Proteins.Journal of chemical information and modeling · 2025Article
- Context-dependent effect of polyethylene glycol on the structure and dynamics of hirudin.Biophysical journal · 2025Article
- Phosphorylation of disordered proteins tunes local and global intramolecular interactions.Biophysical journal · 2024Article
- Emergent microenvironments of nucleoli.Nucleus (Austin, Tex.) · 2024Review
- Physics-Based Machine Learning Trains Hamiltonians and Decodes the Sequence-Conformation Relation in the Disordered Proteome.Journal of chemical theory and computation · 2024Article
- Article
- Notch1 Phase Separation Coupled Percolation facilitates target gene expression and enhancer looping.Scientific reports · 2024Article
- Beyond monopole electrostatics in regulating conformations of intrinsically disordered proteins.PNAS nexus · 2024Article
- Design of intrinsically disordered protein variants with diverse structural properties.Science advances · 2024Article
24 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Intrinsically disordered regions (IDRs) play important roles in proteins that regulate gene expression. A prominent example is the intracellular domain of the Notch receptor (NICD), which regulates the transcription of Notch-responsive genes. The NICD sequence includes an intrinsically disordered RAM region and a conserved ankyrin (ANK) domain. The 111-residue RAM region mediates bivalent interactions of NICD with the transcription factor CSL. Although the sequence of RAM is poorly conserved, the linear patterning of oppositely charged residues shows minimal variation. The conformational properties of polyampholytic IDRs are governed as much by linear charge patterning as by overall charge content. Here, we used sequence design to assess how changing the charge patterning within RAM affects its conformational properties, the affinity of NICD to CSL, and Notch transcriptional activity. Increased segregation of oppositely charged residues leads to linear decreases in the global dimensions of RAM and decreases the affinity of a construct including a C-terminal ANK domain (RAMANK) for CSL. Increasing charge segregation from WT RAM sharply decreases transcriptional activation for all permutants. Activation also decreases for some, but not all, permutants with low charge segregation, although there is considerable variation. Our results suggest that the RAM linker is more than a passive tether, contributing local and/or long-range sequence features that modulate interactions within NICD and with downstream components of the Notch pathway. We propose that sequence features within IDRs have evolved to ensure an optimal balance of sequence-encoded conformational properties, interaction strengths, and cellular activities.
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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.