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Self-regulation of the nuclear pore complex enables clogging-free crowded transport

Nuclear pore complexes (NPCs) are the main conduits for macromolecular transport into and out of the nucleus of eukaryotic cells. The central component of the NPC transport mechanism is an assembly of intrinsically disordered proteins (IDPs) that fills the NPC channel. The channel interior is furthe...

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Autores principales: Zheng, Tiantian, Zilman, Anton
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9963888/
https://www.ncbi.nlm.nih.gov/pubmed/36757893
http://dx.doi.org/10.1073/pnas.2212874120
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author Zheng, Tiantian
Zilman, Anton
author_facet Zheng, Tiantian
Zilman, Anton
author_sort Zheng, Tiantian
collection PubMed
description Nuclear pore complexes (NPCs) are the main conduits for macromolecular transport into and out of the nucleus of eukaryotic cells. The central component of the NPC transport mechanism is an assembly of intrinsically disordered proteins (IDPs) that fills the NPC channel. The channel interior is further crowded by large numbers of simultaneously translocating cargo-carrying and free transport proteins. How the NPC can efficiently, rapidly, and selectively transport varied cargoes in such crowded conditions remains ill understood. Past experimental results suggest that the NPC is surprisingly resistant to clogging and that transport may even become faster and more efficient as the concentration of transport protein increases. To understand the mechanisms behind these puzzling observations, we construct a computational model of the NPC comprising only a minimal set of commonly accepted consensus features. This model qualitatively reproduces the previous experimental results and identifies self-regulating mechanisms that relieve crowding. We show that some of the crowding-alleviating mechanisms—such as preventing saturation of the bulk flux—are “robust” and rely on very general properties of crowded dynamics in confined channels, pertaining to a broad class of selective transport nanopores. By contrast, the counterintuitive ability of the NPC to leverage crowding to achieve more efficient single-molecule translocation is “fine-tuned” and relies on the particular spatial architecture of the IDP assembly in the NPC channel.
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spelling pubmed-99638882023-08-09 Self-regulation of the nuclear pore complex enables clogging-free crowded transport Zheng, Tiantian Zilman, Anton Proc Natl Acad Sci U S A Physical Sciences Nuclear pore complexes (NPCs) are the main conduits for macromolecular transport into and out of the nucleus of eukaryotic cells. The central component of the NPC transport mechanism is an assembly of intrinsically disordered proteins (IDPs) that fills the NPC channel. The channel interior is further crowded by large numbers of simultaneously translocating cargo-carrying and free transport proteins. How the NPC can efficiently, rapidly, and selectively transport varied cargoes in such crowded conditions remains ill understood. Past experimental results suggest that the NPC is surprisingly resistant to clogging and that transport may even become faster and more efficient as the concentration of transport protein increases. To understand the mechanisms behind these puzzling observations, we construct a computational model of the NPC comprising only a minimal set of commonly accepted consensus features. This model qualitatively reproduces the previous experimental results and identifies self-regulating mechanisms that relieve crowding. We show that some of the crowding-alleviating mechanisms—such as preventing saturation of the bulk flux—are “robust” and rely on very general properties of crowded dynamics in confined channels, pertaining to a broad class of selective transport nanopores. By contrast, the counterintuitive ability of the NPC to leverage crowding to achieve more efficient single-molecule translocation is “fine-tuned” and relies on the particular spatial architecture of the IDP assembly in the NPC channel. National Academy of Sciences 2023-02-09 2023-02-14 /pmc/articles/PMC9963888/ /pubmed/36757893 http://dx.doi.org/10.1073/pnas.2212874120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Physical Sciences
Zheng, Tiantian
Zilman, Anton
Self-regulation of the nuclear pore complex enables clogging-free crowded transport
title Self-regulation of the nuclear pore complex enables clogging-free crowded transport
title_full Self-regulation of the nuclear pore complex enables clogging-free crowded transport
title_fullStr Self-regulation of the nuclear pore complex enables clogging-free crowded transport
title_full_unstemmed Self-regulation of the nuclear pore complex enables clogging-free crowded transport
title_short Self-regulation of the nuclear pore complex enables clogging-free crowded transport
title_sort self-regulation of the nuclear pore complex enables clogging-free crowded transport
topic Physical Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9963888/
https://www.ncbi.nlm.nih.gov/pubmed/36757893
http://dx.doi.org/10.1073/pnas.2212874120
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