Visualizing the disordered nuclear transport machinery in situ

Miao Yu, Maziar Heidari, Sofya Mikhaleva, Piau Siong Tan, Sara Mingu, Hao Ruan, Christopher D. Reinkemeier, Agnieszka Obarska-Kosinska, Marc Siggel, Martin Beck, Gerhard Hummer () and Edward A. Lemke ()
Additional contact information
Miao Yu: Biocenter, Johannes Gutenberg University Mainz
Maziar Heidari: Max Planck Institute of Biophysics
Sofya Mikhaleva: Biocenter, Johannes Gutenberg University Mainz
Piau Siong Tan: Structural and Computational Biology, European Molecular Biology Laboratory
Sara Mingu: Biocenter, Johannes Gutenberg University Mainz
Hao Ruan: Biocenter, Johannes Gutenberg University Mainz
Christopher D. Reinkemeier: Biocenter, Johannes Gutenberg University Mainz
Agnieszka Obarska-Kosinska: Max Planck Institute of Biophysics
Marc Siggel: Max Planck Institute of Biophysics
Martin Beck: Max Planck Institute of Biophysics
Gerhard Hummer: Max Planck Institute of Biophysics
Edward A. Lemke: Biocenter, Johannes Gutenberg University Mainz

Nature, 2023, vol. 617, issue 7959, 162-169

Abstract: Abstract The approximately 120 MDa mammalian nuclear pore complex (NPC) acts as a gatekeeper for the transport between the nucleus and cytosol1. The central channel of the NPC is filled with hundreds of intrinsically disordered proteins (IDPs) called FG-nucleoporins (FG-NUPs)2,3. Although the structure of the NPC scaffold has been resolved in remarkable detail, the actual transport machinery built up by FG-NUPs—about 50 MDa—is depicted as an approximately 60-nm hole in even highly resolved tomograms and/or structures computed with artificial intelligence4–11. Here we directly probed conformations of the vital FG-NUP98 inside NPCs in live cells and in permeabilized cells with an intact transport machinery by using a synthetic biology-enabled site-specific small-molecule labelling approach paired with highly time-resolved fluorescence microscopy. Single permeabilized cell measurements of the distance distribution of FG-NUP98 segments combined with coarse-grained molecular simulations of the NPC allowed us to map the uncharted molecular environment inside the nanosized transport channel. We determined that the channel provides—in the terminology of the Flory polymer theory12—a ‘good solvent’ environment. This enables the FG domain to adopt expanded conformations and thus control transport between the nucleus and cytoplasm. With more than 30% of the proteome being formed from IDPs, our study opens a window into resolving disorder–function relationships of IDPs in situ, which are important in various processes, such as cellular signalling, phase separation, ageing and viral entry.

Date: 2023
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DOI: 10.1038/s41586-023-05990-0

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