Structural basis of recognition of monopartite and bipartite nuclear localization sequences by mammalian importin-α11Edited by K. Nagai

Fontes, Marcos R.M.; Teh, Trazel; Kobe, Boštjan

doi:10.1006/jmbi.2000.3642

Cited by 363 publications

(489 citation statements)

References 41 publications

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“…Co-crystal structures of both S. cerevisiae and M. musculus importin-a have been solved in complex with various NLS peptides (52)(53)(54)(55)(56)(57)(58)(59). The three-dimensional structures reveal that NLS peptides bind specifically in two binding grooves created by flexible armadillo (ARM) motifs in the central domain of importin-a (54, 55).…”

Section: Classical Nls Sequencesmentioning

confidence: 99%

“…These grooves interact specifically with the basic, positively charged residues of the cNLS through hydrophobic and electrostatic interactions (3). Between these two binding pockets is a linker-binding region that interacts with the NLS peptide backbone (52,55,57). Changes to specific residues within each of these three regions of importin-a disrupt the nuclear localization and binding of cNLScargoes to importin-a (60,61).…”

Section: Classical Nls Sequencesmentioning

confidence: 99%

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Nuclear localization signals and human disease

McLane

Corbett

2009

IUBMB Life

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SummaryIn eukaryotic cells, the physical separation of the genetic material in the nucleus from the translation and signaling machinery in the cytoplasm by the nuclear envelope creates a requirement for a mechanism through which macromolecules can enter or exit the nucleus as necessary. Nucleocytoplasmic transport involves the specific recognition of cargo molecules by transport receptors in one compartment followed by the physical relocation of that cargo into the other compartment through regulated pores that perforate the nuclear envelope. The recognition of protein cargoes by their transport receptors occurs via amino acid sequences in cargo proteins called nuclear targeting signals. Both nuclear import and export of proteins are highly regulated processes that control, not only what cargo can enter and/or exit the nucleus, but also when in the cell cycle and in what cell type, the cargo can be transported. Deregulation of the nuclear transport of specific cargoes has been linked to numerous cancers and developmental disorders highlighting the importance of understanding the mechanisms underlying nucleocytoplasmic transport and particularly the modulation of the specific interactions between transporter receptors and nuclear targeting signals within target cargo proteins.2009 IUBMB IUBMB Life, 61(7): [697][698][699][700][701][702][703][704][705][706] 2009

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Section: Classical Nls Sequencesmentioning

confidence: 99%

Section: Classical Nls Sequencesmentioning

confidence: 99%

Nuclear localization signals and human disease

McLane

Corbett

2009

IUBMB Life

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“…To determine whether rapid turnover of Hac1p also requires its nuclear localization, we first examined the function of a potential nuclear localization sequence (NLS) located at or near the N-terminal end of the bZIP domain of the protein ( Figure 5A). This sequence, 29 RKRAKTK 35 , contains a cNLS consensus motif (KR/KxR/K; Fontes et al, 2000). Site-directed mutagenesis using the QuikChange PCR method (Wang and Malcolm, 1999) was used to substitute alanine residues for either the first two or all five basic residues of the NLS to generate the NLS3A and NLS6A mutations ( Figure 5A).…”

Section: Degradation Of Hac1p Correlates With Its Nuclear Localizationmentioning

confidence: 99%

SCF^Cdc4-mediated Degradation of the Hac1p Transcription Factor Regulates the Unfolded Protein Response inSaccharomyces cerevisiae

Pal

Chan

Helfenbaum

et al. 2007

MBoC

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The Saccharomyces cerevisiae basic leucine zipper transcription factor Hac1p is synthesized in response to the accumulation of unfolded polypeptides in the lumen of the endoplasmic reticulum (ER), and it is responsible for up-regulation of ϳ5% of all yeast genes, including ER-resident chaperones and protein-folding catalysts. Hac1p is one of the most short-lived yeast proteins, having a half-life of ϳ1.5 min. Here, we have shown that Hac1p harbors a functional PEST degron and that degradation of Hac1p by the proteasome involves the E2 ubiquitin-conjugating enzyme Ubc3/Cdc34p and the SCF Cdc4 E3 complex. Consistent with the known nuclear localization of Cdc4p, rapid degradation of Hac1p requires the presence of a functional nuclear localization sequence, which we demonstrated to involve basic residues in the sequence 29 RKRAKTK 35 . Two-hybrid analysis demonstrated that the PEST-dependent interaction of Hac1p with Cdc4p requires Ser146 and Ser149. Turnover of Hac1p may be dependent on transcription because it is inhibited in cell mutants lacking Srb10 kinase, a component of the SRB/mediator module of the RNA polymerase II holoenzyme. Stabilization of Hac1p by point mutation or deletion, or as the consequence of defects in components of the degradation pathway, results in increased unfolded protein response element-dependent transcription and improved cell viability under ER stress conditions. INTRODUCTIONIn eukaryotic cells, the endoplasmic reticulum (ER) is the portal for newly synthesized proteins destined for all compartments of the exocytic and endocytic pathways as well as for the cell surface and the extracellular space. Transport along the exocytic pathway requires that passenger proteins are correctly folded and assembled (Gething et al., 1986; for review, see Ellgaard and Helenius, 2003), a process that is assisted by molecular chaperones and folding catalysts resident in the ER lumen (for review, see van Anken and Braakman, 2005). The concentrations of these components in the ER are adjusted according to need by the unfolded protein response (UPR; Kozutsumi et al., 1988;Mori et al., 1992; for review, see Kaufman, 1999;Ma and Hendershot, 2001;Patil and Walter, 2001;Schrö der and Kaufman, 2005). The UPR regulates the transcription of ϳ5% of the open reading frames in the Saccharomyces cerevisiae genome, many of which encode proteins with functions involved in diverse processes, including protein translocation, glycosylation, folding and degradation, lipid/inositol metabolism, vesicular trafficking, vacuolar protein sorting, and cell wall biogenesis (Travers et al., 2000).The yeast unfolded protein response (UPR) involves two unique participants, the Ire1p transmembrane receptor kinase/endonuclease (Cox et al., 1993;Mori et al., 1993), and the basic leucine zipper (bZip) transcription factor Hac1p Mori et al., 1996), which transactivates genes bearing UPRE elements (Mori et al., 1992(Mori et al., , 1998Patil and Walter, 2004). HAC1 mRNA is synthesized constitutively as a precursor bearing a 252-nucleotid...

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“…In this study, we detected one NLS at the N-terminus of pericentrin. The classical NLS is characterized by one or two clusters of basic amino acids separated by a linker and recognized by importin α [31]. However, the NLS of pericentrin (from amino acids 8 to 42) consists of three clusters of basic amino acids and all of the three clusters are essential for its nuclear localization.…”

Section: Discussionmentioning

confidence: 99%

“…The NLS-deficient mutant and NESs-deficient mutant of full-length pericentrin were generated by site-directed mutagenesis. The truncated mutants PCNT , PCNT [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] , PCNT [6][7][8][9][10][11][12][13] , PCNT [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] and PCNT [34][35][36][37][38][39][40][41]…”

Section: Plasmid Constructionmentioning

confidence: 99%

Pericentrin contains five NESs and an NLS essential for its nucleocytoplasmic trafficking during the cell cycle

Liu

Zhuo

et al. 2010

Cell Res

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Pericentrin, a conserved centrosomal component, provides the structural scaffold to anchor numerous centrosomal proteins, and thus plays an essential role in the organization and function of the centrosome and the mitotic spindle. Although pericentrin was shown to localize in the cytoplasm and reported to be sensitive to leptomycin B (LMB), a specific inhibitor of Crm1, the regions within pericentrin that serve as signals for transporting in and out of the nucleus have not yet been identified. In this study, we identified five novel nuclear export signals (NESs) in pericentrin with diverse export activities. All of the five NESs could bind to Crm1 in a LMB-sensitive way when mediating the nuclear export of pericentrin. We also demonstrated that the region of amino acids 8-42 in pericentrin contains a tripartite nuclear localization signal (NLS) consisting of three clusters of basic amino acids. The NLS of pericentrin binds to importin β directly or via the adaptor importin α to form the import complex, which could be disrupted by RanQ69L, a dominant-negative Ran GTPase possessing high affinity for importin β. Furthermore, we found that mutation of the NESs in full-length pericentrin results in both nuclear and cytoplasmic localization, and mutation of the NLS abolishes the nuclear import of pericentrin. On the basis of these results, we suggest that the NESs and NLS of pericentrin are essential for its subcellular localization and nucleocytoplasmic trafficking during the cell cycle.

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Structural basis of recognition of monopartite and bipartite nuclear localization sequences by mammalian importin-α11Edited by K. Nagai

Cited by 363 publications

References 41 publications

Nuclear localization signals and human disease

Nuclear localization signals and human disease

SCF^Cdc4-mediated Degradation of the Hac1p Transcription Factor Regulates the Unfolded Protein Response inSaccharomyces cerevisiae

Pericentrin contains five NESs and an NLS essential for its nucleocytoplasmic trafficking during the cell cycle

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Structural basis of recognition of monopartite and bipartite nuclear localization sequences by mammalian importin-α11Edited by K. Nagai

Cited by 363 publications

References 41 publications

Nuclear localization signals and human disease

Nuclear localization signals and human disease

SCFCdc4-mediated Degradation of the Hac1p Transcription Factor Regulates the Unfolded Protein Response inSaccharomyces cerevisiae

Pericentrin contains five NESs and an NLS essential for its nucleocytoplasmic trafficking during the cell cycle

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SCF^Cdc4-mediated Degradation of the Hac1p Transcription Factor Regulates the Unfolded Protein Response inSaccharomyces cerevisiae