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Towards a minimal model of the nuclear pore complex

Davis, Luke Kristopher; (2021) Towards a minimal model of the nuclear pore complex. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The transport of macromolecules between the nucleus and cytoplasm is controlled by nuclear pore complexes (NPC) that permeate the nuclear envelope. The NPC allows small (∼ 5 nm diameter) molecules to passively diffuse in and out of the nucleus but hinders the transport of larger material through the presence of sticky intrinsically disordered proteins (FG Nups) that occlude the inner pore channel. Through complexation with nuclear transport receptors (NTRs), which have an affinity to the FG motifs in the Nups, large cargoes are able to overcome the NPC permeability barrier. Our physical understanding of how FG Nups and NTRs give rise to selective transport remains incomplete. In this thesis, the behaviour of FG Nups and NTRs is probed using coarse-grained physical modelling approaches that treat the FG Nups and NTRs in a rather minimal fashion, and that are implemented in computer simulations and analytical models. By treating the FG Nups as homopolymers and comparing simulations with various experimental data it is here found that they behave very similarly to idealized polymer chains. Secondly, when this model is extended to recently developed biomimetic nanopores it can account for the morphology as seen in those experiments. In this nanopore system, the resealing dynamics of the FG Nups were three orders of magnitude faster than typical transport event times (~ 1 ms). The homopolymer model is further expanded to include various NTRs in an FG Nup polymer film, and simulations reveal the emergence of phase separation of different NTRs at physiologically relevant densities. Finally, the roles of sequence and surface heterogeneity of the FG Nups and NTRs on binding, diffusion in an FG Nup melt, and uptake in a nanopore are explored using modelling approaches that account for such heterogeneity at minimal complexity. Overall, this thesis makes progress towards a minimal model of the NPC.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Towards a minimal model of the nuclear pore complex
Event: UCL (University College London)
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10118968
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