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Review
. 2015 Feb 15;466(1):13-28.
doi: 10.1042/BJ20141186.

Diversification of importin-α isoforms in cellular trafficking and disease states

Ruth A Pumroy  1 , Gino Cingolani  1
Affiliations
Review

Diversification of importin-α isoforms in cellular trafficking and disease states

Ruth A Pumroy et al. Biochem J. .

Abstract

The human genome encodes seven isoforms of importin α which are grouped into three subfamilies known as α1, α2 and α3. All isoforms share a fundamentally conserved architecture that consists of an N-terminal, autoinhibitory, importin-β-binding (IBB) domain and a C-terminal Arm (Armadillo)-core that associates with nuclear localization signal (NLS) cargoes. Despite striking similarity in amino acid sequence and 3D structure, importin-α isoforms display remarkable substrate specificity in vivo. In the present review, we look at key differences among importin-α isoforms and provide a comprehensive inventory of known viral and cellular cargoes that have been shown to associate preferentially with specific isoforms. We illustrate how the diversification of the adaptor importin α into seven isoforms expands the dynamic range and regulatory control of nucleocytoplasmic transport, offering unexpected opportunities for pharmacological intervention. The emerging view of importin α is that of a key signalling molecule, with isoforms that confer preferential nuclear entry and spatiotemporal specificity on viral and cellular cargoes directly linked to human diseases.

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Figures

Figure 1
Figure 1. The classic nuclear import pathway
Importin β, importin α and an NLS-cargo assembly in the cytoplasm travel through the nuclear pore. The disassembly of the import complex is started by the binding of RanGTP to importin β, which causes release of the IBB domain. Disassembly of the NLS-cargo from importin α is a concerted effort of the IBB domain, the nucleoporin Nup50 and the importin α-recycling factor CAS. The empty importins are recycled back to the cytoplasm, where they are released to restart the import cycle via hydrolysis of RanGTP.
Figure 2
Figure 2. The classic nuclear import complex
The diagram is based on the structure of human importin β (beige) bound to the IBB domain (dark blue; PDB 1QGK) and mouse importin α2 (cyan) bound to the nucleoplasmin NLS (grey; PDB 1EJY). The N-terminus and C-terminus of each structure are noted with an ‘N’ or ‘C’, respectively. The illustration was produced using the Chimera program [150].
Figure 3
Figure 3. Evolution of importin α
From left to right is a schematic diagram of the evolution of the importin-α gene in Saccharomyces cerevisiae, Drosophila sp. and Homo sapiens; the scale bar represents 0.1 residue changes per amino acid position. Phylogenetic trees for Drosophila and human isoforms were generated with ClustalW [15] and TreeView [151]. The electrostatic surface charge distribution {determined using APBS Tools [152] and PyMol (PyMOL Molecular Graphics System, Version 1.3r1, Schrödinger L. L. C.)} is shown for the isoforms determined crystallographically, namely importin α1 (PDB 4E4 V), importin α3 (PDB 4UAE), importin α5 (PDB 3TJ3), importin α6 (PDB 4U2X) and importin α7 (PDB 4UAD). NS: Not Solved.
Figure 4
Figure 4. Arm-core structure and conservation
(A) (i) Structure of the Arm-core of importin α3 (PDB 4UAE) with α-helices shown as cylinders. Schematic diagram of (ii) a canonical Arm and (iii) the degenerate Arm 1, missing helix H1 and of (iv) HEAT repeat (equivalent to Arm 5), and (v) Arm 10, which adopts an open conformation in a structure of importin α5 (PDB 2JDQ). (B) Conservation of the NLS-binding surface of importin-α isoforms. Residues identical in all human isoforms were mapped on to a surface representation of importin α1 (PDB 4E4 V). Identical and non-conserved residues are coloured blue and grey, respectively.
Figure 5
Figure 5. Autoinhibition of Arm-core by the IBB domain
(A) Model of the full-length importin α (grey surface) autoinhibited by the IBB domain (blue). The structure shown represents the full-length Kap60 extracted from PDB 1WA5. (B) Alignment of the basic residues of the IBB domain that interact with the major and minor NLS-binding sites of importin α isoforms and Kap60.
Figure 6
Figure 6. Cellular strategies of regulating importin-α isoforms
Schematic diagrams of: (A) microRNA-mediated regulation of importin-α expression; (B) regulation of import by sequestration of importin α; (C) regulation of import by degradation of importin α; and (D) regulation of import by post-translational modifications of importin α.
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References

    1. Cingolani G, Petosa C, Weis K, Muller CW. Structure of importin-beta bound to the IBB domain of importin-alpha. Nature. 1999;399:221–229. - PubMed
    1. Goldfarb DS, Corbett AH, Mason DA, Harreman MT, Adam SA. Importin alpha: a multipurpose nuclear-transport receptor. Trends Cell Biol. 2004;14:505–514. - PubMed
    1. Lott K, Cingolani G. The importin beta binding domain as a master regulator of nucleocytoplasmic transport. Biochim. Biophys. Acta. 2011;1813:1578–1592. - PMC - PubMed
    1. Jans DA, Xiao CY, Lam MH. Nuclear targeting signal recognition: a key control point in nuclear transport? Bioessays. 2000;22:532–544. - PubMed
    1. Gorlich D, Kutay U. Transport between the cell nucleus and the cytoplasm. Annu. Rev. Cell Dev. Biol. 1999;15:607–660. - PubMed

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