Exquisite biological machines operate in synchrony to orchestrate cellular life. A particularly vital nanomachine pertains to the nuclear pore complex (NPC) that safeguards the cell nucleus against the unsolicited leakage of substances into or out of it. NPC access is exclusively confined to signal-specific protein cargoes that are selectively trafficked between the nucleus and cytoplasm to sustain cell function. Otherwise, NPC malfunction is associated with disease. Still, the modus operandi of the NPC remains unresolved after two decades of work. As a case in point, the NPC interior is filled with intrinsically disordered proteins termed phenylalanine-glycine nucleoporins (FG Nups) that elude structural characterization. Little is also known as to how soluble transport receptors termed karyopherins (or Kaps) facilitate the rapid passage of specific cargoes through the FG Nups. In our lab, we combine nanoscale, biophysical and cellular approaches to unravel the functional principles of this fascinating biomolecular system. This has provided key insights into: (1) the dynamic behavior of the NPC transport barrier; (2) the regulation of NPC transport speed and selectivity; and (3) the role of Kaps in fortifying NPC barrier function, amongst others. Consequently, we find that NPC malfunction and nucleocytoplasmic leakage result from poor Kap enrichment in vivo.

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