ArticleProceedings of the National Academy of Sciences of the United States of America2022
Multivalency enables unidirectional switch-like competition between intrinsically disordered proteins.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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26 citing papers in PubMed, 35 citations in OpenAlex.
- De Novo Design of Multivalent α/β-Peptides Mimicking Transcription Factors Targeting the CBP KIX Domain.Chemistry (Weinheim an der Bergstrasse, Germany) · 2026Article
- Sequence-encoded differences in the conformational ensembles of CITED transcriptional activation domains impact coactivator binding.Protein science : a publication of the Protein Society · 2026Article
- Dynamic control of IDP interaction network via diverse binding pathways.Nature communications · 2026Article
- 14-3-3ζ interacts with DNA-binding domain of FOXO3a and competitively dissociates DNA by dual-motif tethering.Nature communications · 2026Article
- Sequence-encoded differences in the conformational ensembles of CITED transcriptional activation domains impact coactivator binding.bioRxiv : the preprint server for biology · 2026Article
- Linker Length and Composition within Disordered Binding Motifs Modulates the Avidity and Reversibility of a Multivalent Protein Interaction Switch.Journal of molecular biology · 2025Article
- The BRD4-nucleosome interaction is enhanced modestly and non-selectively by histone acetylation.Nucleic acids research · 2025Article
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- From molecular descriptions to cellular functions of intrinsically disordered protein regions.Biophysics reviews · 2024Review
- Site-directed allostery perturbation to probe the negative regulation of hypoxia inducible factor-1α.RSC chemical biology · 2024Article
- Protein structure-function continuum model: Emerging nexuses between specificity, evolution, and structure.Protein science : a publication of the Protein Society · 2024Review
- The molecular basis for cellular function of intrinsically disordered protein regions.Nature reviews. Molecular cell biology · 2024Review
- Commonly asked questions about transcriptional activation domains.Current opinion in structural biology · 2024Review
- Tutorial: a guide for the selection of fast and accurate computational tools for the prediction of intrinsic disorder in proteins.Nature protocols · 2023Review
- From Immunogenic Peptides to Intrinsically Disordered Proteins.Israel journal of chemistry · 2023Article
- The Rous sarcoma virus Gag Polyprotein Forms Biomolecular Condensates Driven by Intrinsically-disordered Regions.Journal of molecular biology · 2023Article
- Protein Binding: A Fuzzy Concept.Life (Basel, Switzerland) · 2023Article
- NMR insights into dynamic, multivalent interactions of intrinsically disordered regions: from discrete complexes to condensates.Essays in biochemistry · 2022Article
- The biophysics of disordered proteins from the point of view of single-molecule fluorescence spectroscopy.Essays in biochemistry · 2022Article
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3 authors at 1 institution in 1 country.
Funding
Abstract
Intrinsically disordered proteins must compete for binding to common regulatory targets to carry out their biological functions. Previously, we showed that the activation domains of two disordered proteins, the transcription factor HIF-1α and its negative regulator CITED2, function as a unidirectional, allosteric molecular switch to control transcription of critical adaptive genes under conditions of oxygen deprivation. These proteins achieve transcriptional control by competing for binding to the TAZ1 domain of the transcriptional coactivators CREB-binding protein (CBP) and p300 (CREB: cyclic-AMP response element binding protein). To characterize the mechanistic details behind this molecular switch, we used solution NMR spectroscopy and complementary biophysical methods to determine the contributions of individual binding motifs in CITED2 to the overall competition process. An N-terminal region of the CITED2 activation domain, which forms a helix when bound to TAZ1, plays a critical role in initiating competition with HIF-1α by enabling formation of a ternary complex in a process that is highly dependent on the dynamics and disorder of the competing partners. Two other conserved binding motifs in CITED2, the LPEL motif and an aromatic/hydrophobic motif that we term ϕC, function synergistically to enhance binding of CITED2 and inhibit rebinding of HIF-1α. The apparent unidirectionality of competition between HIF-1α and CITED2 is lost when one or more of these binding regions is altered by truncation or mutation of the CITED2 peptide. Our findings illustrate the complexity of molecular interactions involving disordered proteins containing multivalent interaction motifs and provide insight into the unique mechanisms by which disordered proteins compete for occupancy of common molecular targets within the cell.
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