Trends in Cell Biology
Volume 14, Issue 9, September 2004, Pages 505-514
Journal home page for Trends in Cell Biology

Importin α: a multipurpose nuclear-transport receptor

https://doi.org/10.1016/j.tcb.2004.07.016Get rights and content

The importin α/β heterodimer targets hundreds of proteins to the nuclear-pore complex (NPC) and facilitates their translocation across the nuclear envelope. Importin α binds to classical nuclear localization signal (cNLS)-containing proteins and links them to importin β, the karyopherin that ferries the ternary complex through the NPC. A second karyopherin, the exportin CAS, recycles importin α back to the cytoplasm. In this article, we discuss control mechanisms that importin α exerts over the assembly and disassembly of the ternary complex and we describe how new groups of importin α genes arose during the evolution of metazoan animals to function in development and differentiation. We also describe activities of importin α that seem to be distinct from its housekeeping functions in nuclear transport.

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.

References (73)

  • M.T. Harreman

    The auto-inhibitory function of importin alpha is essential in vivo

    J. Biol. Chem.

    (2003)
  • D. Gilchrist

    Accelerating the rate of disassembly of karyopherin.cargo complexes

    J. Biol. Chem.

    (2002)
  • D. Gilchrist et al.

    Molecular basis for the rapid dissociation of nuclear localization signals from karyopherin alpha in the nucleoplasm

    J. Biol. Chem.

    (2003)
  • M. Rexach et al.

    Protein import into nuclei: association and dissociation reactions involving transport substrate, transport factors, and nucleoporins

    Cell

    (1995)
  • U. Kutay

    Export of importin alpha from the nucleus is mediated by a specific nuclear transport factor

    Cell

    (1997)
  • J.K. Hood et al.

    Cse1p is required for export of Srp1p/importin-alpha from the nucleus in Saccharomyces cerevisiae

    J. Biol. Chem.

    (1998)
  • M.E. Lindsay

    Npap60/Nup50 is a tri-stable switch that stimulates importin-alpha:beta-mediated nuclear protein import

    Cell

    (2002)
  • M. Kohler

    Cloning of two novel human importin-alpha subunits and analysis of the expression pattern of the importin-alpha protein family

    FEBS Lett.

    (1997)
  • E. Mathe

    Importin-alpha3 is required at multiple stages of Drosophila development and has a role in the completion of oogenesis

    Dev. Biol.

    (2000)
  • M.A. Andrade

    Comparison of ARM and HEAT protein repeats

    J. Mol. Biol.

    (2001)
  • K. Melen

    Importin alpha nuclear localization signal binding sites for STAT1, STAT2, and influenza A virus nucleoprotein

    J. Biol. Chem.

    (2003)
  • M. Kohler

    Adenoviral E1A protein nuclear import is preferentially mediated by importin alpha3 in vitro

    Virology

    (2001)
  • C.J. Jiang

    Molecular cloning of a novel importin alpha homologue from rice, by which constitutive photomorphogenic 1 (COP1) nuclear localization signal (NLS)-protein is preferentially nuclear imported

    J. Biol. Chem.

    (2001)
  • L. Tsuji

    Identification of novel homologues of mouse importin alpha, the alpha subunit of the nuclear pore-targeting complex, and their tissue-specific expression

    FEBS Lett.

    (1997)
  • M.G. Prieve

    The nuclear localization signal of lymphoid enhancer factor-1 is recognized by two differentially expressed Srp1-nuclear localization sequence receptor proteins

    J. Biol. Chem.

    (1996)
  • M. Giarre

    Patterns of importin-alpha expression during Drosophila spermatogenesis

    J. Struct. Biol.

    (2002)
  • M. Gorjanacz

    Importin-alpha 2 is critically required for the assembly of ring canals during Drosophila oogenesis

    Dev. Biol.

    (2002)
  • B.B. Quimby et al.

    The small GTPase Ran: interpreting the signs

    Curr. Opin. Cell Biol.

    (2003)
  • O.J. Gruss

    Ran induces spindle assembly by reversing the inhibitory effect of importin alpha on TPX2 activity

    Cell

    (2001)
  • G. Cingolani

    Nuclear import factors importin alpha and importin beta undergo mutually induced conformational changes upon association

    FEBS Lett.

    (2000)
  • S.J. Gamblin et al.

    Nuclear transport: what a kary-on!

    Structure Fold Des.

    (1999)
  • H. Fried et al.

    Nucleocytoplasmic transport: taking an inventory

    Cell. Mol. Life Sci.

    (2003)
  • I.G. Macara

    Transport into and out of the nucleus

    Microbiol. Mol. Biol. Rev.

    (2001)
  • S. Jakel et al.

    Importin beta, transportin, RanBP5 and RanBP7 mediate nuclear import of ribosomal proteins in mammalian cells

    EMBO J.

    (1998)
  • N. Mosammaparast

    Nuclear import of histone H2A and H2B is mediated by a network of karyopherins

    J. Cell Biol.

    (2001)
  • P. Muhlhausser

    Multiple pathways contribute to nuclear import of core histones

    EMBO Rep.

    (2001)
  • Cited by (0)

    View full text