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The nuclear pore permeability barrier – physical concepts and a biosynthetic approach to understand and exploit the unique selectivity of a natural macromolecular sieve

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Mechanisms of selective entry into the nucleus

Nuclear pore complexes (NPCs) control the passage of large molecules between the nucleus and the cytoplasm. Research revealing possible supramolecular mechanisms could be important in advancing targeted therapies for viral infections.

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The nucleus of a living cell is the treasure chest protecting the genetic code for manufacture of proteins that serve virtually all functions. While protective isolation is necessary, so is communication with the rest of the cell. NPCs are self-assembled structures made up of proteins called nucleoporins. They perforate the nuclear envelope and facilitate the selective passage of molecules. Small molecules readily diffuse through the NPCs, but the movement of large molecules is tightly regulated. Specialised nucleoporins with repeating amino acid sequences of phenylalanine (F) and glycine (G) play an important role in selective gating. Large molecules bind to nuclear transport receptors (NTRs) that in turn bind to the FG domains found in high density along the NPC channel walls. Scientists initiated the EU-funded NUCLEAR PORE (The nuclear pore permeability barrier – Physical concepts and a biosynthetic approach to understand and exploit the unique selectivity of a natural macromolecular sieve) project to enhance understanding of the supramolecular structure of the nuclear pore permeability barrier and the mechanism of selective transport across it. The team studied binding of NTRs to FG domains using advanced experimental techniques (quartz crystal microbalance and spectroscopic ellipsometry). Researchers exploited ultrathin films of naturally occurring and artificially designed FG domains as well-defined model systems of the permeability barrier, to evaluate sequence effects on FG domain assembly and NTR binding. Results demonstrated a universal binding behaviour that was not well described by conventional binding models and provided possible explanations and implications for nuclear transport. Comparison with computational modelling by collaborating scientists revealed that this behaviour is determined by generic physical properties of FG domains such as flexibility and spatial confinement, whereas the detailed chemical and structural heterogeneity is not a critical factor. NUCLEAR PORE outcomes have advanced understanding of the mechanisms of selective gating of nuclear transport, enabling several aspects of recently proposed models to be tested. Given that viral binding to FG domains is a way to pass through the nuclear barrier, such mechanistic understanding could have direct application to targeted therapies for some viral infections.

Keywords

Nucleus, nuclear pore, viral infections, nucleoporins, nuclear transport receptors, permeability barrier

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