Novel Binding of the Mitotic Regulator TPX2 (Target Protein for Xenopus Kinesin-like Protein 2) to Importin-α

Giesecke, Astrid; Stewart, Murray

doi:10.1074/jbc.m110.102343

Cited by 83 publications

(113 citation statements)

References 42 publications

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“…Surprisingly, position P 4 is occupied by an Ala, a residue not commonly found in the context of an NLS (35). Unlike NLSs that bind exclusively (or preferentially) to the importin ␣ minor NLS site (47,72,73,77), HSV-1 pUL15 NLS inserts a Lys at P 2 Ј (Lys-185) as opposed to an Arg, possibly explaining the weak affinity for this site. The general features of pUL15 NLS recognition by importin ␣ resemble those observed for the classical of SV40 NLS (44,45).…”

Section: Data Collectionmentioning

confidence: 99%

Divergent Evolution of Nuclear Localization Signal Sequences in Herpesvirus Terminase Subunits

Sankhala

Lokareddy

Cingolani

2016

Journal of Biological Chemistry

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The tripartite terminase complex of herpesviruses assembles in the cytoplasm of infected cells and exploits the host nuclear import machinery to gain access to the nucleus, where capsid assembly and genome-packaging occur. Here we analyzed the structure and conservation of nuclear localization signal (NLS) sequences previously identified in herpes simplex virus 1 (HSV-1) large terminase and human cytomegalovirus (HCMV) small terminase. We found a monopartite NLS at the N terminus of large terminase, flanking the ATPase domain, that is conserved only in ␣-herpesviruses. In contrast, small terminase exposes a classical NLS at the far C terminus of its helical structure that is conserved only in two genera of the ␤-subfamily and absent in ␣-and ␥-herpesviruses. In addition, we predicted a classical NLS in the third terminase subunit that is partially conserved among herpesviruses. Bioinformatic analysis revealed that both location and potency of NLSs in terminase subunits evolved more rapidly than the rest of the amino acid sequence despite the selective pressure to keep terminase gene products active and localized in the nucleus. We propose that swapping NLSs among terminase subunits is a regulatory mechanism that allows different herpesviruses to regulate the kinetics of terminase nuclear import, reflecting a mechanism of virus:host adaptation.

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Section: Data Collectionmentioning

confidence: 99%

Divergent Evolution of Nuclear Localization Signal Sequences in Herpesvirus Terminase Subunits

Sankhala

Lokareddy

Cingolani

2016

Journal of Biological Chemistry

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“…The A89 and B54 sequences do not match either of these two consensus sequences. On the other hand, the binding of the NLSs from TPX2 (target protein for Xenopus laevis kinesin-like protein 2) (Giesecke and Stewart, 2010) and hPLSCR4 to the minor NLS binding site has been observed structurally. A89 and B54 NLSs make use not only of the usual minor-site cavities (positions P19 to P49) but also have more extended contacts in the C-terminal region of rImpa1a.…”

Section: Sequences (Krx[w/f/y]xxaf and [R/p]xxkr[k/r][-d/e]mentioning

confidence: 99%

Crystal Structure of Rice Importin-α and Structural Basis of Its Interaction with Plant-Specific Nuclear Localization Signals

et al. 2012

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In the classical nucleocytoplasmic import pathway, nuclear localization signals (NLSs) in cargo proteins are recognized by the import receptor importin-a. Importin-a has two separate NLS binding sites (the major and the minor site), both of which recognize positively charged amino acid clusters in NLSs. Little is known about the molecular basis of the unique features of the classical nuclear import pathway in plants. We determined the crystal structure of rice (Oryza sativa) importin-a1a at 2-Å resolution. The structure reveals that the autoinhibitory mechanism mediated by the importin-b binding domain of importin-a operates in plants, with NLS-mimicking sequences binding to both minor and major NLS binding sites. Consistent with yeast and mammalian proteins, rice importin-a binds the prototypical NLS from simian virus 40 large T-antigen preferentially at the major NLS binding site. We show that two NLSs, previously described as plant specific, bind to and are functional with plant, mammalian, and yeast importin-a proteins but interact with rice importin-a more strongly. The crystal structures of their complexes with rice importin-a show that they bind to the minor NLS binding site. By contrast, the crystal structures of their complexes with mouse (Mus musculus) importin-a show preferential binding to the major NLS binding site. Our results reveal the molecular basis of a number of features of the classical nuclear transport pathway specific to plants.

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“…23 A short central sequence in TPX2 is involved in importin-α binding, and along the nuclear localization signals (NLS) these regions are important for regulation of subcellular localization during the cell cycle. 24 The 43-aa domain at the N-terminus is sufficient for activation of Aurora-A. This domain does not provoke global conformational changes in the kinase, but a helical fragment of TPX2 (residues 30-43; Fig.…”

Section: Tpx2 Structure and Regulationmentioning

confidence: 99%

Mitotic Stress and Chromosomal Instability in Cancer: The Case for TPX2

Castro

Malumbres

2012

Genes & Cancer

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Cell cycle deregulation is a common motif in human cancer, and multiple therapeutic strategies are aimed to prevent tumor cell proliferation. Whereas most current therapies are designed to arrest cell cycle progression either in G1/S or in mitosis, new proposals include targeting the intrinsic chromosomal instability (CIN, an increased rate of gain or losses of chromosomes during cell division) or aneuploidy (a genomic composition that differs from diploid) that many tumor cells display. Why tumors cells are chromosomally unstable or aneuploid and what are the consequences of these alterations are not completely clear at present. Several mitotic regulators are overexpressed as a consequence of oncogenic alterations, and they are likely to alter the proper regulation of chromosome segregation in cancer cells. In this review, we propose the relevance of TPX2, a mitotic regulator involved in the formation of the mitotic spindle, in oncogene-induced mitotic stress. This protein, as well as its partner Aurora-A, is frequently overexpressed in human cancer, and its deregulation may participate not only in chromosome numeric aberrations but also in other forms of genomic instability in cancer cells.

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Novel Binding of the Mitotic Regulator TPX2 (Target Protein for Xenopus Kinesin-like Protein 2) to Importin-α

Cited by 83 publications

References 42 publications

Divergent Evolution of Nuclear Localization Signal Sequences in Herpesvirus Terminase Subunits

Divergent Evolution of Nuclear Localization Signal Sequences in Herpesvirus Terminase Subunits

Crystal Structure of Rice Importin-α and Structural Basis of Its Interaction with Plant-Specific Nuclear Localization Signals

Mitotic Stress and Chromosomal Instability in Cancer: The Case for TPX2

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