FG-Nup sequence length polydispersity enhances selectivity of nuclear pore complex translocation

Area of Science:

• Biophysics
• Cell Biology
• Structural Biology

Background:

• The nuclear pore complex (NPC) regulates transport between the nucleus and cytoplasm.
• FG-nucleoporins (FG-Nups) form a selective barrier within the NPC's central channel.
• FG-Nup sequence length exhibits polydispersity, with variations across the NPC.

Purpose of the Study:

• To investigate the functional role of FG-Nup length polydispersity in NPC transport.
• To compare transport efficiency and selectivity between homogeneous and inhomogeneous NPC models.
• To elucidate the biophysical mechanisms underlying FG-Nup mediated selective transport.

Main Methods:

• Development of a minimal, coarse-grained model of the NPC.
• Utilizing Langevin dynamics simulations to model cargo translocation.
• Comparing a homogeneous NPC (h-NPC) with uniform FG-Nup lengths to an inhomogeneous NPC (ih-NPC) with varied FG-Nup lengths.

Main Results:

• The inhomogeneous NPC (ih-NPC) demonstrated significantly higher passage probabilities for karyopherin-bound tracers (up to 90% increase).
• The ih-NPC exhibited enhanced selectivity compared to the h-NPC.
• Tracer translocation was facilitated by a 'handover' mechanism between FG-Nups, with shorter interior FG-Nups increasing binding contacts.

Conclusions:

• FG-Nup polydispersity, specifically shorter FG-Nups in the central pore, enhances NPC selectivity and transport efficiency.
• The findings provide a biophysical explanation for the evolutionary advantage of FG-Nup length variation in selective nuclear transport.