Trends in Cell Biology
Importin α: a multipurpose nuclear-transport receptor
Section snippets
The structure of importin α and its function in nuclear transport
Importin αs are composed of a flexible N-terminal importin-β-binding (IBB) domain and a highly structured domain comprised of ten tandem armadillo (ARM) repeats 7, 8, 9 (Box 1). The helical ARM repeats assemble into a twisted slug-like structure, whose belly serves as the cNLS-binding groove. The exportin CAS binds to the tenth ARM repeat. The flexible IBB domain interacts either in trans with importin β or in cis with the cNLS-binding groove. Through these interactions, the IBB domain acts as
Importin α forms a ternary complex with cNLS cargo and importin β
The formation of the importin-α/β–cNLS cargo ternary complex is the first step in the nuclear transport of hundreds of different nuclear proteins, and, as such, is tightly regulated (Box 1). The N-terminal IBB domain serves a dual role. It binds to importin β to target the complex to the NPC for translocation 16, 17 but it also contains an autoinhibitory sequence that mimics a cNLS and regulates binding of cNLS cargo to the ARM domain of importin α 18, 19. When importin α is not bound to
Evolutionary origins of the importin α gene family
The importin α gene family has undergone considerable expansion during the course of eukaryotic evolution. Whereas the yeast S. cerevisiae genome encodes a single importin α, the human genome encodes six genes that fall into three phylogenetically distinct groups, the α1s, α2s and α3s (Figure 3). The organization of the importin α gene family into three distinct groups supports a unifying nomenclature that greatly simplifies, and, in fact, provides a principled approach to the interpretation of
Importin α gene family members in animal development
The occurrence of importin α2 and α3 clades in metazoan animals is consistent with their having evolved to perform animal specific roles. Drosophila melanogaster is a suitable model genetic system to test this hypothesis because fruit flies contain a single representative of each importin α1, α2 and α3 clade. Significant insight has also come from studying the importin αs of Caenorhabditis elegans. Genetic analysis of the animal importin αs is complicated by the fact that all of the α1, α2 and
Drosophila importin α2 has both common and unique roles in gametogenesis
Drosophila importin α2 (Dα2) is highly expressed in the early embryo, presumably from maternal stores, in ovaries and testes, in imaginal discs and in other somatic adult tissues such as the brain 40, 52, 53. Homozygous Dα2 mutant flies develop normally to adulthood; however, they exhibit defects in gametogenesis and are sterile 40, 52, 54. Thus, Dα2 is not required for development of the soma in flies. The nonessential role of Dα2 in somatic tissues is presumably redundant with the activities
Drosophila importin α3 has multiple important roles in development
Dα3 has a more essential and general role in development than Dα2 because it is essential for both larval and adult development [55]. Furthermore, it has an interesting role in the development of the heat shock response in Drosophila [56]. The transcription factor dHSF is responsible for the heat-induced transcription of heat shock proteins. Early embryos cannot mount a proper heat shock response because dHSF is restricted to the cytoplasm until after the twelfth cell cycle, when it
In vivo analysis of nematode importin αs
The nematode C. elegans provides a second model genetic system to investigate the roles of importin αs in development. Although key features of the C. elegans importin α gene family are unique, their individual expression patterns and mutant phenotypes exhibit parallels to Drosophila. C. elegans worms express one conventional importin α3 (IMA-3) and two divergent αs (IMA-1 and IMA-2). IMA-2 might actually be a divergent importin α2, which, like Dα2, is strongly expressed in germ cells [57] and
Additional cellular roles for importin α
Recently, it has become evident that importin αs serve transport independent roles in the assembly of macromolecular structures. In addition to the role of Drosophila importin α2 in ring canal biogenesis described above [54], genetic analyses of yeast importin α mutants identified several alleles that confer defects in chromosome and nuclear segregation, altered mitotic spindle structure and deficits in the ubiquitin-mediated protein degradation pathway 60, 61, 62, 63. The molecular mechanisms
Concluding remarks
Importin α is an ARM domain protein that serves as a binding scaffold to link cNLS cargos to importin β. Much more than just a rigid adaptor, importin α contains a flexible IBB domain that controls cNLS binding and participates in both the assembly and the disassembly of the ternary complex. Future studies will focus on how importin α coordinates the concerted series of conformational switches and control mechanisms that ensure the high fidelity, directionality and efficiency of the importin
Acknowledgements
We thank members of our laboratories for helpful suggestions. Work in the authors’ laboratories is supported by NIH GM40362, March of Dimes 1FY01–313, and NSF MCB 0110972 (D.S.G) and NIH GM58728–05 (A.H.C). We dedicate this contribution to our friend and colleague Alec Hodel, who is dearly missed.
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