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Peer-reviewedCC BY-NC-NDNature Communications

Mapping interactions between disordered regions reveals promiscuity in biomolecular condensate formation

  • Atar Gilat1,2
  • Alexander I. Alexandrov2,3
  • Benjamin Dubreuil2,4
  • Emmanuel D. Levy5,6
6 affiliations
  1. 1Department of Chemical and Biological Physics, Weizmann Institute of Science, Rehovot, Israel
  2. 2Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel
  3. 3Department of Molecular and Cellular Biology, University of Geneva, Geneva, Switzerland
  4. 4Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
  5. 5Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel. [email protected]
  6. 6Department of Molecular and Cellular Biology, University of Geneva, Geneva, Switzerland. [email protected]
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Abstract

Intrinsically-disordered regions (IDRs) promote intracellular phase separation and the formation of biomolecular condensates through interactions encoded in their primary sequence. While these condensates form spatially distinct assemblies in cells, it is unclear whether such specificity can be conferred by IDRs alone. Indeed, IDRs exhibit high conformational flexibility whereas specificity in protein recognition is generally associated with well-defined 3D structures. To characterize IDR-IDR interactions and assess their ability to mediate self-specific partitioning, we developed a synthetic system of Multivalent IDRs forming Constitutive DROPlets ( micDROP ). We investigated ten natural IDRs that underwent phase separation in micDROP . These IDRs exhibited a wide range of saturation concentrations in vivo , which correlated well with their total sequence stickiness. We then probed IDR-IDR specificity by co-expressing pairs of IDRs fused to homologous scaffolds that did not co-assemble. We observed a high degree of promiscuity, particularly among IDRs from the proteins Ddx4, DYRK3, ERα, FUS, hnRNPA1, HspB8, RBM14 and TAF15, whereas TDP43 and UBQ2 formed spatially distinct condensates regardless of their partner. Further investigation revealed the short and conserved α-helical segment of TDP43’s IDR was governing its specific self-recognition. Our findings imply that IDRs can tune their phase separation propensity through sequence composition, while their formation of discrete condensates likely requires additional cellular or structural determinants. Abstract Figure

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Cite

BibTeXRIS
BibTeX
@article{gilat2026mapping,
  title = {{Mapping interactions between disordered regions reveals promiscuity in biomolecular condensate formation}},
  author = {Atar Gilat and Alexander I. Alexandrov and Benjamin Dubreuil and Emmanuel D. Levy},
  journal = {Nature Communications},
  year = {2026},
  month = jun,
  doi = {10.1038/s41467-026-73800-y},
  url = {https://doi.org/10.1038/s41467-026-73800-y},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Mapping interactions between disordered regions reveals promiscuity in biomolecular condensate formation
AU  - Atar Gilat
AU  - Alexander I. Alexandrov
AU  - Benjamin Dubreuil
AU  - Emmanuel D. Levy
PY  - 2026
DA  - 2026/06/02
JO  - Nature Communications
DO  - 10.1038/s41467-026-73800-y
UR  - https://doi.org/10.1038/s41467-026-73800-y
AB  - Intrinsically-disordered regions (IDRs) promote intracellular phase separation and the formation of biomolecular condensates through interactions encoded in their primary sequence. While these condensates form spatially distinct assemblies in cells, it is unclear whether such specificity can be conferred by IDRs alone. Indeed, IDRs exhibit high conformational flexibility whereas specificity in protein recognition is generally associated with well-defined 3D structures. To characterize IDR-IDR interactions and assess their ability to mediate self-specific partitioning, we developed a synthetic system of Multivalent IDRs forming Constitutive DROPlets ( micDROP ). We investigated ten natural IDRs that underwent phase separation in micDROP . These IDRs exhibited a wide range of saturation concentrations in vivo , which correlated well with their total sequence stickiness. We then probed IDR-IDR specificity by co-expressing pairs of IDRs fused to homologous scaffolds that did not co-assemble. We observed a high degree of promiscuity, particularly among IDRs from the proteins Ddx4, DYRK3, ERα, FUS, hnRNPA1, HspB8, RBM14 and TAF15, whereas TDP43 and UBQ2 formed spatially distinct condensates regardless of their partner. Further investigation revealed the short and conserved α-helical segment of TDP43’s IDR was governing its specific self-recognition. Our findings imply that IDRs can tune their phase separation propensity through sequence composition, while their formation of discrete condensates likely requires additional cellular or structural determinants. Abstract Figure
SN  - 2041-1723
ER  -