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Differential conformational expansion of NUP98-HOXA9 oncoprotein from nanosized assemblies to macrophases

Author

Listed:
  • Hao Ruan

    (Johannes Gutenberg University Mainz, Biocenter
    Institute of Molecular Biology postdoctoral program)

  • Rodrigo F. Dillenburg

    (Max-Planck Institute for Polymer Research)

  • Elnaz Hosseini

    (Institute of Molecular Biology (IMB gGmbH))

  • Sina Wittmann

    (Institute of Molecular Biology (IMB gGmbH)
    Institute for quantitative and computational biosciences)

  • Martin Girard

    (Max-Planck Institute for Polymer Research
    Institute for quantitative and computational biosciences)

  • Edward A. Lemke

    (Johannes Gutenberg University Mainz, Biocenter
    Institute of Molecular Biology (IMB gGmbH))

Abstract

Transcription factors (TFs) play a central role in gene regulation by binding to specific DNA sequences and orchestrating the transcriptional machinery. A majority of eukaryotic TFs have a block copolymer architecture, with at least one block being a folded DNA interaction domain, and another block being highly enriched in intrinsic disorder. In this study, we focus on NUP98-HOXA9 (NHA9), a chimeric TF implicated in leukemogenesis. By integrating experiments and simulations, we examine the structural dynamics of NHA9’s FG domain across assembly states. We find that the FG domain has different conformational compactness in the monomeric, oligomeric, and densely packed condensate state. Notably, the oligomeric state exhibits micelle-like organization with non-fixed stoichiometry, with the DNA-binding domain exposed at the periphery. These findings offer molecular insight into the phase behaviour of NHA9 and highlight dynamic conformational transitions of intrinsically disordered regions during molecular assembly, with implications for understanding transcriptional regulation in cancer.

Suggested Citation

  • Hao Ruan & Rodrigo F. Dillenburg & Elnaz Hosseini & Sina Wittmann & Martin Girard & Edward A. Lemke, 2025. "Differential conformational expansion of NUP98-HOXA9 oncoprotein from nanosized assemblies to macrophases," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-66327-1
    DOI: 10.1038/s41467-025-66327-1
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