期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 135, 期 6, 页码 2321-2329出版社
AMER CHEMICAL SOC
DOI: 10.1021/ja311080j
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资金
- National Institutes of Health [GM073439]
- National Science Foundation [CHE-1213452]
- Direct For Mathematical & Physical Scien
- Division Of Chemistry [1213452] Funding Source: National Science Foundation
The nuclear pore complex (NPC) is the proteinaceous nanopore that solely mediates molecular transport across the nuclear envelope between the nucleus and cytoplasm of a eukaryotic cell. Small molecules (<40 kDa) diffuse through the large pore of this multiprotein complex. A passively impermeable macromolecule tagged with a signal peptide is chaperoned through the nanopore by nuclear transport receptors (e.g., importins) owing to their interactions with barrier-forming proteins. Presently, this bimodal transport mechanism is not well understood and is described by controversial models. Herein, we report on a dynamic and spatially resolved mechanism for NPC-mediated molecular transport through nanoscale central and peripheral routes with distinct permeabilities. Specifically, we develop a nanogap-based approach of scanning electrochemical microscopy to precisely measure the extremely high permeability of the nuclear envelope to a small probe molecule, (ferrocenylmethyl)trimethylammonium. Effective medium theories indicate that the passive permeability of 5.9 X 10(-2) cm/s corresponds to the free diffusion of the probe molecule through similar to 22 nanopores with a radius of 24 nm and a length of 35 nm. Peripheral routes are blocked by wheat germ agglutinin to yield 2-fold lower permeability for 17 nm-radius central routes. This lectin is also used in fluorescence assays to find that importins facilitate the transport of signal-tagged albumin mainly through the 7 nm-thick peripheral route rather than through the sufficiently large central route. We propose that this spatial selectivity is regulated by the conformational changes in barrier-forming proteins that transiently and locally expand the impermeably thin peripheral route while blocking the central route.
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