The Molecular Mechanism of Transport Selectivity across the Nuclear Pore Complex

Aleksei Aksimentiev, University of Illinois at Urbana-Champaign

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Aleksei Aksimentiev, Jejoong Yoo, Christopher Maffeo, Maxim Belkin, Manish Shankla, Shu-Han Chao, Chen-Yu Li, Karl Decker, James Wilson, Dmitrii Kochkov, Scott Michael Slone, Shalini Lovis, Alex Finnegan, Han-Yi Chou, David Winogradoff, Wei Si, John Zeiders, Lauren Johnson, Shidi Zhao

The nuclear pore complex (NPC) regulates the transport of all RNA and proteins across the nuclear envelope of eukaryotic cells. Large molecules can only cross the nuclear pore when escorted by nuclear transport proteins known to interact with the central element of an NPC—the nucleoporin, or Nup, which is a network of disordered proteins rich in hydrophobic phenylalanine-glycine (FG) repeats. The results of prior experiments suggest that the intrinsically-disordered FG-Nup network undergoes a phase transition, forming a three-dimensional hydrogel-like mesh. Several mutually exclusive theoretical models have been proposed to account for selective transport through NPCs, however, the microscopic mechanism remains unknown. Several years ago, the Dekker group at Delft Technical University developed an experimental assay that faithfully represents the selective transport of proteins through NPCs. In this assay, the protein transport is characterized by measurement of the ionic current flowing through a solid-state nanopore decorated with nucleoporins. Recent unpublished data from the Dekker group revealed a dramatic effect of point mutations on selectivity of the NPC transport, which may hold the key to solving the NPC transport puzzle. Experiment alone, however, is not sufficient to determine the microscopic processes enabling selective cargo transport. Here, we propose a set of molecular dynamic simulations that will uncover the actual three-dimensional architecture of the central mesh of the NPC and provide a physical description of selective nuclear transport. The outcome of this project may offer new insights into the molecular origin of human diseases and have implications for the development of gene therapy treatments.