Endocrine Abstracts

Nuclear pore complexes (NPCs) facilitate the transport of macromolecular cargoes across the nuclear envelope by carrier molecules. The energy for this active transport mechanism is provided by the Ras-family GTPase, Ran, that orchestrates most nuclear trafficking cycles. The RanGEF (RCC1) is located in the nucleus while its GAP is located in the cytoplasm. The nuclear import of steroids, bound to their receptor, is mediated by importins alpha and beta. In the cytoplasm, importin-alpha binds to the nuclear import sequence (NLS) of the receptor and to importin-beta, which is the principal carrier for nuclear protein import. This complex is then transported through NPCs and requires interactions with nuclear pore proteins (nucleoporins). Once the cargo-carrier complex has traversed to the nucleus through the central channel of NPCs, nuclear RanGTP dissociates the importins from their cargo. After cargo release, the importin-beta:RanGTP complex, together with importin-alpha complexed with its nuclear export factor CAS:RanGTP, are recycled to the cytoplasm, when RanGAP stimulates the RanGTPase, releasing both for another round of import. The NPCs are huge macromolecular assemblies that have roughly 30 X the mass of a ribosome and are based on a central cylindrical body that spans the nuclear envelope, together with cytoplasmic fibrils and a fibrous nuclear basket. NPCs are constructed from multiple copies of the order of 30 different nucleoporins, many of which have FG repeats that are characterized by Phe-rich hydrophobic cores (such as FxFG and GLFG) separated by hydrophilic linkers of variable sequence composition and length. Interactions between transport factors and FG-nucleoporins are important for passage through NPCs, although the precise way in which these interactions function remains controversial. Structural studies of the components of the nuclear trafficking machinery combined with in vitro and in vivo studies are now beginning to give insight into how these processes are co-ordinated.