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Peer-reviewedCC BY-NC-NDProceedings of the National Academy of Sciences

A functional map of the human intrinsically disordered proteome

  • Iva Pritišanac1,2,3,4,5
  • T. Reid Alderson6,7,8
  • Đesika Kolarić6,7,9
  • Taraneh Zarin1,8
  • Shuting Xie1,8
  • Alex Xijie Lu1,10,8
  • Aqsa Alam1,8
  • Abdullah Maqsood4,5
  • Ji‐Young Youn11,4,5
  • Julie Deborah Forman-Kay12,4,5
  • Alan M Moses1,10,8
12 affiliations
  1. 1Department of Cell and Systems Biology, University of Toronto
  2. 2Department of Medicinal Chemistry, Otto Loewi Research Center, Medical University of Graz
  3. 3Helmholtz Munich, Computational Health Center, Institute of Computational Biology
  4. 4Program in Molecular Medicine, The Hospital for Sick Children
  5. 5The Hospital for Sick Children
  6. 6Helmholtz Munich, Molecular Targets and Therapeutics Center, Institute of Structural Biology
  7. 7Technical University of Munich School of Natural Sciences, Department of Bioscience, Bavarian Nuclear Magnetic Resonance Center, Technical University of Munich
  8. 8University of Toronto
  9. 9Medical University of Graz
  10. 10Department of Computer Science, University of Toronto
  11. 11Department of Molecular Genetics, University of Toronto
  12. 12Department of Biochemistry, The University of Toronto
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Abstract

Intrinsically disordered regions (IDRs) represent at least one-third of the human proteome and defy the established structure-function paradigm. Because IDRs often have limited positional sequence conservation, the functional classification of IDRs using standard bioinformatics is generally not possible. Here, we show that evolutionarily conserved molecular features of the intrinsically disordered human proteome (IDR-ome), termed evolutionary signatures, enable classification and prediction of IDR functions. Hierarchical clustering of the human IDR-ome based on evolutionary signatures reveals strong enrichments for frequently studied functions of IDRs in transcription and RNA processing, as well as diverse, rarely studied functions, ranging from sub-cellular localization and biomolecular condensates to cellular signaling, transmembrane transport, and the constitution of the cytoskeleton. We exploit the information that is encoded within evolutionary conservation of molecular features to propose functional annotations for every IDR in the human proteome, inspect the conserved molecular features that correlate with different functions, and discover frequently co-occurring IDR functions on the proteome scale. Further, we identify patterns of evolutionary conserved molecular features of IDRs within proteins of unknown function and disease-risk genes for conditions such as cancer and developmental disorders. Our map of the human IDR-ome should be a valuable resource that aids in the discovery of new IDR biology.

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Cite

BibTeXRIS
BibTeX
@article{pritisanac2026functional,
  title = {{A functional map of the human intrinsically disordered proteome}},
  author = {Iva Pritišanac and T. Reid Alderson and Đesika Kolarić and Taraneh Zarin and Shuting Xie and Alex Xijie Lu and Aqsa Alam and Abdullah Maqsood and Ji‐Young Youn and Julie Deborah Forman-Kay and Alan M Moses},
  journal = {Proceedings of the National Academy of Sciences},
  year = {2026},
  month = may,
  doi = {10.1073/pnas.2604562123},
  url = {https://doi.org/10.1073/pnas.2604562123},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - A functional map of the human intrinsically disordered proteome
AU  - Iva Pritišanac
AU  - T. Reid Alderson
AU  - Đesika Kolarić
AU  - Taraneh Zarin
AU  - Shuting Xie
AU  - Alex Xijie Lu
AU  - Aqsa Alam
AU  - Abdullah Maqsood
AU  - Ji‐Young Youn
AU  - Julie Deborah Forman-Kay
AU  - Alan M Moses
PY  - 2026
DA  - 2026/05/18
JO  - Proceedings of the National Academy of Sciences
DO  - 10.1073/pnas.2604562123
UR  - https://doi.org/10.1073/pnas.2604562123
AB  - Intrinsically disordered regions (IDRs) represent at least one-third of the human proteome and defy the established structure-function paradigm. Because IDRs often have limited positional sequence conservation, the functional classification of IDRs using standard bioinformatics is generally not possible. Here, we show that evolutionarily conserved molecular features of the intrinsically disordered human proteome (IDR-ome), termed evolutionary signatures, enable classification and prediction of IDR functions. Hierarchical clustering of the human IDR-ome based on evolutionary signatures reveals strong enrichments for frequently studied functions of IDRs in transcription and RNA processing, as well as diverse, rarely studied functions, ranging from sub-cellular localization and biomolecular condensates to cellular signaling, transmembrane transport, and the constitution of the cytoskeleton. We exploit the information that is encoded within evolutionary conservation of molecular features to propose functional annotations for every IDR in the human proteome, inspect the conserved molecular features that correlate with different functions, and discover frequently co-occurring IDR functions on the proteome scale. Further, we identify patterns of evolutionary conserved molecular features of IDRs within proteins of unknown function and disease-risk genes for conditions such as cancer and developmental disorders. Our map of the human IDR-ome should be a valuable resource that aids in the discovery of new IDR biology.
SN  - 0027-8424
SN  - 1091-6490
ER  -