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Phosphate-dependent nuclear export via a non-classical NES class recognized by exportin Msn5

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  • Ho Yee Joyce Fung

    (UT Southwestern Medical Center
    UT Southwestern Medical Center)

  • Sanraj R. Mittal

    (The Rockefeller University)

  • Ashley B. Niesman

    (UT Southwestern Medical Center
    UT Southwestern Medical Center)

  • Jenny Jiou

    (UT Southwestern Medical Center
    The Walter and Eliza Hall Institute of Medical Research)

  • Binita Shakya

    (UT Southwestern Medical Center
    University of Nebraska Medical Center)

  • Takuya Yoshizawa

    (UT Southwestern Medical Center
    Ltd)

  • Ahmet E. Cansizoglu

    (UT Southwestern Medical Center
    EMD Serono Research & Development Institute)

  • Michael P. Rout

    (The Rockefeller University)

  • Yuh Min Chook

    (UT Southwestern Medical Center)

Abstract

Gene expression in response to environmental stimuli is dependent on nuclear localization of key signaling components, which can be tightly regulated by phosphorylation. This is exemplified by the phosphate-sensing transcription factor Pho4, which requires phosphorylation for nuclear export by the yeast exportin Msn5. Here, we present a high resolution cryogenic-electron microscopy structure showing the phosphorylated 35-residue nuclear export signal of Pho4, which binds the concave surface of Msn5 through two Pho4 phospho-serines that align with two Msn5 basic patches. These findings characterize a mechanism of phosphate-specific recognition mediated by a non-classical signal distinct from that for Exportin-1. Furthermore, the discovery that unliganded Msn5 is autoinhibited explains the positive cooperativity of Pho4/Ran-binding and proposes a mechanism for Pho4’s release in the cytoplasm. These findings advance our understanding of the diversity of signals that drive nuclear export and how cargo phosphorylation is crucial in regulating nuclear transport and controlling cellular signaling pathways.

Suggested Citation

  • Ho Yee Joyce Fung & Sanraj R. Mittal & Ashley B. Niesman & Jenny Jiou & Binita Shakya & Takuya Yoshizawa & Ahmet E. Cansizoglu & Michael P. Rout & Yuh Min Chook, 2025. "Phosphate-dependent nuclear export via a non-classical NES class recognized by exportin Msn5," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57752-3
    DOI: 10.1038/s41467-025-57752-3
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    References listed on IDEAS

    as
    1. Josh Abramson & Jonas Adler & Jack Dunger & Richard Evans & Tim Green & Alexander Pritzel & Olaf Ronneberger & Lindsay Willmore & Andrew J. Ballard & Joshua Bambrick & Sebastian W. Bodenstein & David , 2024. "Addendum: Accurate structure prediction of biomolecular interactions with AlphaFold 3," Nature, Nature, vol. 636(8042), pages 4-4, December.
    2. Xiuhua Dong & Anindita Biswas & Katherine E. Süel & Laurie K. Jackson & Rita Martinez & Hongmei Gu & Yuh Min Chook, 2009. "Erratum: Structural basis for leucine-rich nuclear export signal recognition by CRM1," Nature, Nature, vol. 461(7263), pages 550-550, September.
    3. Shunichi Kosugi & Hiroshi Yanagawa & Ryohei Terauchi & Satoshi Tabata, 2014. "NESmapper: Accurate Prediction of Leucine-Rich Nuclear Export Signals Using Activity-Based Profiles," PLOS Computational Biology, Public Library of Science, vol. 10(9), pages 1-11, September.
    4. Atlanta G. Cook & Noemi Fukuhara & Martin Jinek & Elena Conti, 2009. "Structures of the tRNA export factor in the nuclear and cytosolic states," Nature, Nature, vol. 461(7260), pages 60-65, September.
    5. Xiuhua Dong & Anindita Biswas & Katherine E. Süel & Laurie K. Jackson & Rita Martinez & Hongmei Gu & Yuh Min Chook, 2009. "Structural basis for leucine-rich nuclear export signal recognition by CRM1," Nature, Nature, vol. 458(7242), pages 1136-1141, April.
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