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<p>The RNA genome of measles virus is encapsidated by the nucleoprotein within a helical nucleocapsid that serves as&#xa0;a template for both transcription and replication. The intrinsically disordered domain of the nucleoprotein (N<sub>TAIL</sub>) is essential for binding the polymerase complex responsible for viral transcription and replication. As for many IDPs, binding of N<sub>TAIL</sub> occurs through a short molecular recognition element (MoRE) that folds upon binding, with the majority of N<sub>TAIL</sub> remaining disordered. Although N<sub>TAIL</sub> regions far from the MoRE influence the binding affinity, interactions between them and the MoRE have not been investigated in depth. Relying on photo-induced electron transfer (PET) experiments between tryptophan and cysteine pairs placed at different positions in the protein under varying salt and pH conditions, combined with analytical models, simulations, and coevolutionary analysis, we identified transient interactions between two disordered regions distant in sequence, which dominate N<sub>TAIL</sub> dynamics, and regulate the conformational preferences of both the MoRE and the entire N<sub>TAIL</sub> domain. We propose mechanisms by which these non-local interactions may regulate binding to the measles phosphoprotein, polymerase recruitment, and ultimately viral transcription and replication. Our findings may be extended to other IDPs, where non-local intra-protein interactions affect the conformational preferences of intermolecular binding sites.</p>

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Transient non-local interactions dominate the dynamics of measles virus NTAIL

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月6日

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  • Lillian Otteson,
  • Gabor Nagy,
  • John Kunkel,
  • Gerdenis Kodis,
  • Lars V. Bock,
  • Christophe Bignon,
  • Sonia Longhi,
  • Wenwei Zheng,
  • Helmut Grubmüller,
  • Andrea C. Vaiana,
  • Sara M. Vaiana

摘要

The RNA genome of measles virus is encapsidated by the nucleoprotein within a helical nucleocapsid that serves as a template for both transcription and replication. The intrinsically disordered domain of the nucleoprotein (NTAIL) is essential for binding the polymerase complex responsible for viral transcription and replication. As for many IDPs, binding of NTAIL occurs through a short molecular recognition element (MoRE) that folds upon binding, with the majority of NTAIL remaining disordered. Although NTAIL regions far from the MoRE influence the binding affinity, interactions between them and the MoRE have not been investigated in depth. Relying on photo-induced electron transfer (PET) experiments between tryptophan and cysteine pairs placed at different positions in the protein under varying salt and pH conditions, combined with analytical models, simulations, and coevolutionary analysis, we identified transient interactions between two disordered regions distant in sequence, which dominate NTAIL dynamics, and regulate the conformational preferences of both the MoRE and the entire NTAIL domain. We propose mechanisms by which these non-local interactions may regulate binding to the measles phosphoprotein, polymerase recruitment, and ultimately viral transcription and replication. Our findings may be extended to other IDPs, where non-local intra-protein interactions affect the conformational preferences of intermolecular binding sites.