The integrative model enables us to visualize how the flexible FG chains lining the NPC’s central channel filter molecular traffic between the nucleus and the cytoplasm at picosecond resolution, well beyond the capabilities of any existing imaging technology.
#NPC #transport

The integrative model enables us to visualize how the flexible FG chains lining the NPC’s central channel filter molecular traffic between the nucleus and the cytoplasm at picosecond resolution, well beyond the capabilities of any existing imaging technology.
#NPC #transport

This was a true team effort across HUJI, UCSF/QBI, Rockefeller, Einstein, Basel, and UCSD/HHMI. Immense thanks to our colleagues and collaborators at the Sali, Rout, Cowburn, Villa and Lim labs.

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Aberrant nucleocytoplasmic transport is associated with disease, from cancer to neurodegeneration and viral infection. A mechanistic, quantitative model opens doors to diagnostics and therapeutic design, for both native pores and their artificial mimics. /

The basic transport mechanism is like buoyancy in water: inside the NPC, flexible FG chains create an entropic push that repels unescorted molecules from the mid-plane. NTRs add molecular ballast via FG binding, counteracting buoyancy and ferrying cargo through.

A key outcome: we identify 10 molecular design features that together yield speed, selectivity, and robustness for nucleocytoplasmic transport through the NPC, and predict how tuning them shifts performance.

The model recapitulates observed selectivities and fluxes across cargo sizes and receptor properties, and explains how massive cargo can still pass quickly when properly escorted.

The model recapitulates observed selectivities and fluxes across cargo sizes and receptor properties, and explains how massive cargo can still pass quickly when properly escorted.

Large cargoes are nonetheless granted passage through the pore if they carry the right “passport”: nuclear transport receptors (NTRs). NTRs make many fast, weak, transient handshakes with FG chains, using a slide-and-exchange mechanism that allows them to glide smoothly from chain to chain.

Our answer centers on an entropic barrier created by a dense, dynamic “forest” of flexible FG-repeat protein chains inside the NPC’s central channel. Large molecular cargoes punch holes in this dynamic thicket, incurring an energetic penalty for free passage through the pore.