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

Ho Yee Joyce Fung, Sanraj R. Mittal, Ashley B. Niesman, Jenny Jiou, Binita Shakya, Takuya Yoshizawa, Ahmet E. Cansizoglu, Michael P. Rout and Yuh Min Chook ()
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Ho Yee Joyce Fung: UT Southwestern Medical Center
Sanraj R. Mittal: The Rockefeller University
Ashley B. Niesman: UT Southwestern Medical Center
Jenny Jiou: UT Southwestern Medical Center
Binita Shakya: UT Southwestern Medical Center
Takuya Yoshizawa: UT Southwestern Medical Center
Ahmet E. Cansizoglu: UT Southwestern Medical Center
Michael P. Rout: The Rockefeller University
Yuh Min Chook: UT Southwestern Medical Center

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-57752-3

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