Pii: S0962-8924(98)01248-3

PII: S0962-8924(98)01248-3 Our current understanding of the dynamics of nuclear import has evolved from the initial identification of the ‘classical nuclear localization signal’ (cNLS), which consists of a short sequence rich in basic amino-acid residues1. Transport of proteins bearing this signal into the nucleus is mediated by a karyopherin a–b1 heterodimeric complex plus additional factors such as the GTPase Ran and its associated protein p10 (NTF2) (reviewed in Refs 2 and 3). The nomenclature for the a–b1 complex remains confusing, owing to its almost coincident identification by several laboratories (see Table 1). Here, we use the general term karyopherin [from the Greek terms karyon meaning nucleus and pher(ein) meaning to bring to or to carry from4] for it most accurately describes a family of receptors that are able to recognize substrates, in either (or both) the nucleoplasm or cytoplasm, and assist in their transport into and out of the nucleus. In the prototypical case, the karyopherin a subunit of the a–b1 dimer binds to the cNLS, and the complex then docks at the nuclear pore complex (NPC) in an energy-independent manner through interactions between karyopherin b1 and (at least) cytoplasmically exposed NPC proteins (nucleoporins) containing characteristic peptide repeats. Subsequent translocation through the NPC and termination of import require energy and the GTPase Ran (see the accompanying hypothesis article by Melchior and Gerace). Ran appears to play a crucial role in maintaining vectorial cargo transport and in regulating the binding and release steps that occur during translocation through the NPC. Ran exists in the cell in two forms, either as Ran–GTP or Ran–GDP. Because of the subcellular localization of several proteins that alter the nucleotide-bound state of Ran, it is likely that the predominant form of Ran in the cytosol is Ran–GDP, whereas in the nucleus the major form is Ran–GTP. Such a gradient of Ran could establish directional transport by creating separate environments in which transport complexes are either assembled or disassembled (reviewed in Refs 5 and 6). Consistent with this idea, the karyopherin b1–a–cNLS complex is stable in the presence of Ran–GDP (i.e. in the cytosol), whereas Ran–GTP promotes its disassembly and the release of substrate (i.e. in the nucleus). In addition to these more global effects, Ran also acts as a molecular switch at sites within the NPC. Here, it is thought that, in concert with p10 (Ref. 7), conversion of the nucleotide-bound state of Ran modulates interactions between the NPC and b1, a and the cNLS-containing cargo in what has been proposed to be a series of association and dissociation reactions that occur as these components step their way through the NPC8. While the karyopherin a–b1 heterodimer is likely to account for the import of cNLS-containing cargo, it has recently been established that an extended family of karyopherin b1-related nuclear transport factors exists. This article describes recent progress in characterizing these proteins. Some members of this family have been shown to be involved directly in transporting specific classes of macromolecules into and out of the nucleus, whereas others have been implicated indirectly in nuclear transport.