Abstract
Nuclear transport receptors (NTRs) mediate nucleocytoplasmic transport via their affinity for unstructured proteins (polymers) in the nuclear pore complex (NPC). Here, we have modeled the effect of NTRs on polymeric structure in the nanopore confinement of the NPC central conduit. The model explicitly takes into account inter- and intramolecular interactions, as well as the finite size of the NTRs (∼20% of the NPC channel diameter). It reproduces various proposed scenarios for the channel structure, ranging from a central polymer condensate (selective phase) to brushlike polymer arrangements localized at the channel wall (virtual gate, reduction of dimensionality), with the transport receptors lining the polymer surface. In addition, it predicts a new structure in which NTRs become an integral part of the transport barrier by forming a cross-linked network with the unstructured proteins stretching across the pore. The model provides specific and distinctive predictions for the equilibrium spatial distributions of NTRs for these different scenarios that can be experimentally verified by, e.g., superresolution fluorescence microscopy. Moreover, it suggests mechanisms by which globular macromolecules (colloidal particles) can cause polymer-coated nanopores to switch between open and closed configurations, a possible explanation of the biological function of the NPC, and suggests potential technological applications for filtration and single-molecule sensing.
Highlights
The nuclear pore complex (NPC) is the sole gate for macromolecular transport between the nucleus and the cytoplasm of eukaryotic cells [1,2,3,4,5,6,7]
The scaffold structure consists of structural nucleoporins and is reasonably well defined, the proteins in the central channel are largely unstructured and disordered, which compromises the results yielded by conventional methods of structure determination that rely on crystal formation and symmetry-facilitated averaging
Having explored the different types of behavior for this simple model system, we investigate whether it is reproduced in a system that more closely resembles the nups in the NPC central channel
Summary
The nuclear pore complex (NPC) is the sole gate for macromolecular transport between the nucleus and the cytoplasm of eukaryotic cells [1,2,3,4,5,6,7] It consists of a large scaffold spanning the nuclear envelope, with an outer diameter of 90–120 nm and a central channel or conduit of diameter 30–50 nm for transport. The scaffold structure consists of structural nucleoporins (nups) and is reasonably well defined, the proteins in the central channel are largely unstructured and disordered, which compromises the results yielded by conventional methods of structure determination that rely on crystal formation and symmetry-facilitated averaging These unstructured proteins are anchored to the NPC scaffold structure and contain multiple repeats of Phe-Gly dipeptides (often referred to as FG nups). All macromolecules (cargos) that are transported through the pore contain a nuclear localization signal or a nuclear export signal that binds to an NTR and the NTR-bound cargo can diffuse through the pore
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