Improving the hole picture: towards a consensus on the mechanism of nuclear transport

Abstract

Nuclear pore complexes (NPCs) mediate the exchange of materials between the nucleoplasm and cytoplasm, playing a key role in the separation of nucleic acids and proteins into their required compartments. The static structure of the NPC is relatively well defined by recent cryo-EM and other studies. The functional roles of dynamic components in the pore of the NPC, phenylalanyl-glycyl (FG) repeat rich nucleoporins, is less clear because of our limited understanding of highly dynamic protein systems. These proteins form a ‘restrained concentrate’ which interacts with and concentrates nuclear transport factors (NTRs) to provide facilitated nucleocytoplasmic transport of cargoes. Very rapid on- and off-rates among FG repeats and NTRs supports extremely fast facilitated transport, close to the rate of macromolecular diffusion in cytoplasm, while complexes without specific interactions are entropically excluded, though details on several aspects of the transport mechanism and FG repeat behaviors remain to be resolved. However, as discussed here, new technical approaches combined with more advanced modeling methods will likely provide an improved dynamic description of NPC transport, potentially at the atomic level in the near future. Such advances are likely to be of major benefit in comprehending the roles the malfunctioning NPC plays in cancer, ageing, viral diseases, and neurodegeneration.

Integrative spatiotemporal map of nucleocytoplasmic transport

“…To plot the results of simulations (which only depend on r) as a function of molecular weight, we assumed that each sphere has a uniform protein density of 1.38 g/cm 3 158 , resulting in . Alternatively, the radius can be interpreted as the Stokes radius of the molecule,, resulting in MW = ( r /6.6) 3 kDa 159 , leading to nearly identical values for the molecular weight.…”

“…The Nuclear Pore Complex (NPC), a large protein assembly spanning the Nuclear Envelope (NE) 1–3 , mediates selective macromolecular traffic between the nucleus and cytoplasm of the eukaryotic cell, a process known as nucleocytoplasmic transport. The NPC is composed of (i) a ring-shaped scaffold consisting of hundreds of protein subunits (nucleoporins or Nups) and (ii) the central transporter consisting of dozens of disordered phenylalanyl-glycyl (FG) rich repeat domains of FG Nups.…”

“…We first studied passive and facilitated diffusion of macromolecular cargo through a single NPC, initially without taking into account the RanGTP cycle (RanGTP-independent transport) 2,3,38,71 . This simplification is justified because RanGTP is not required for modulating the permeability of the NPC to NTR:cargo complexes 88 ; for example, NTRs can facilitate equilibration across the NE independently from RanGTP 89 .…”

“…Biomolecular condensates are loosely defined as micron-scale compartments in eukaryotic cells that lack surrounding membranes, but concentrate biomolecules including proteins and nucleic acids 144 . This rather broad definition includes a diverse group of biophysical systems in different states 3,145,146 . Several transport models propose that the central transporter shares unusual viscoelastic properties with gels, hydrogels, and liquid-liquid phase separations 3,42,147–149 .…”

“…This rather broad definition includes a diverse group of biophysical systems in different states 3,145,146 . Several transport models propose that the central transporter shares unusual viscoelastic properties with gels, hydrogels, and liquid-liquid phase separations 3,42,147–149 . We next consider transport system properties shared with condensates.…”