The cellular environment shapes the nuclear pore complex architecture

Anthony P. Schuller, Matthias Wojtynek, David Mankus, Meltem Tatli, Rafael Kronenberg-Tenga, Saroj G. Regmi, Phat V. Dip, Abigail K. R. Lytton-Jean, Edward J. Brignole, Mary Dasso, Karsten Weis, Ohad Medalia () and Thomas U. Schwartz ()
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Anthony P. Schuller: Massachusetts Institute of Technology
Matthias Wojtynek: University of Zurich
David Mankus: Massachusetts Institute of Technology
Meltem Tatli: University of Zurich
Rafael Kronenberg-Tenga: University of Zurich
Saroj G. Regmi: NIH
Phat V. Dip: Massachusetts Institute of Technology
Abigail K. R. Lytton-Jean: Massachusetts Institute of Technology
Edward J. Brignole: Massachusetts Institute of Technology
Mary Dasso: NIH
Karsten Weis: ETH Zurich
Ohad Medalia: University of Zurich
Thomas U. Schwartz: Massachusetts Institute of Technology

Nature, 2021, vol. 598, issue 7882, 667-671

Abstract: Abstract Nuclear pore complexes (NPCs) create large conduits for cargo transport between the nucleus and cytoplasm across the nuclear envelope (NE)1–3. These multi-megadalton structures are composed of about thirty different nucleoporins that are distributed in three main substructures (the inner, cytoplasmic and nucleoplasmic rings) around the central transport channel4–6. Here we use cryo-electron tomography on DLD-1 cells that were prepared using cryo-focused-ion-beam milling to generate a structural model for the human NPC in its native environment. We show that—compared with previous human NPC models obtained from purified NEs—the inner ring in our model is substantially wider; the volume of the central channel is increased by 75% and the nucleoplasmic and cytoplasmic rings are reorganized. Moreover, the NPC membrane exhibits asymmetry around the inner-ring complex. Using targeted degradation of Nup96, a scaffold nucleoporin of the cytoplasmic and nucleoplasmic rings, we observe the interdependence of each ring in modulating the central channel and maintaining membrane asymmetry. Our findings highlight the inherent flexibility of the NPC and suggest that the cellular environment has a considerable influence on NPC dimensions and architecture.

Date: 2021
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DOI: 10.1038/s41586-021-03985-3

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