A Small Ubiquitin-Related Polypeptide Involved in Targeting RanGAP1 to Nuclear Pore Complex Protein RanBP2

Mahajan, Rohit; Delphin, Christian; Guan, Tinglu; Gerace, Larry; Melchior, Frauke

doi:10.1016/s0092-8674(00)81862-0

Cited by 1,152 publications

(1,081 citation statements)

References 43 publications

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“…On the other hand, it also remains possible that the gel filtration properties of human RanGAP are altered by post-translational modifications, e.g. the attachment of a ubiquitin-like moiety described recently (56,57). Detailed structural analyses, e.g.…”

Section: Discussionmentioning

confidence: 99%

The Acidic C-terminal Domain of rna1p Is Required for the Binding of Ran·GTP and for RanGAP Activity

Haberland¹,

Becker²,

Gerke³

1997

Journal of Biological Chemistry

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The small GTP binding protein Ran is an essential component of the nuclear protein import machinery whose GTPase cycle is regulated by the nuclear guanosine nucleotide exchange factor RCC1 and by the cytosolic GTPase activating protein RanGAP. In the yeasts Schizosaccharomyces pombe and Saccharomyces cerevisiae the RanGAP activity is encoded by the RNA1 genes which are essential for cell viability and nucleocytoplasmic transport in vivo. Although of limited sequence identity the two yeast proteins show a conserved structural organization characterized by an N-terminal domain of eight leucine-rich repeats, motifs implicated in protein-protein interactions, and a C-terminal domain rich in acidic amino acid residues. By analyzing the RanGAP activity of a series of recombinantly expressed rna1p mutant derivatives, we show that the highly acidic sequence in the C-terminal domain of both yeast proteins is indispensable for activating Ran-mediated GTP hydrolysis. Chemical cross-linking reveals that the same sequence in rna1p is required for rna1p⅐Ran complex formation indicating that the loss of GAP activity in the C-terminally truncated rna1p mutants results from an impaired interaction with Ran. The predominant species stabilized through the covalent cross-link is a rna1p⅐Ran heterodimer whose formation requires the GTP-bound conformation of Ran. As the acidic C-terminal domain of rna1p is required for establishing the interaction with Ran, the leucine-rich repeats domain in rna1p is potentially available for additional protein interactions perhaps required for directing a fraction of rna1p to the nuclear pore.The import of karyophilic proteins into the nucleus which occurs through the nuclear pore complex (NPC) 1 is an energydependent process specified by nuclear localization signals (NLSs) on the import substrate (for reviews see Refs. 1-4). Using digitonin-permeabilized HeLa cells as an in vitro transport system, it was shown that the import of substrate proteins is a multistep process depending on four cytosolic factors (5, 6) (for reviews see Refs. 7-10). Two of these factors form a heterodimeric complex serving as the NLS receptor. The smaller 60-kDa subunit of this complex, also known as importin ␣, is responsible for NLS binding, whereas the larger 97-kDa subunit, importin ␤, most likely mediates a targeting of the substrate-NLS receptor complex to the NPC. After docking the entire substrate-receptor complex is thought to travel through the NPC and then to dissociate close to or at the nucleoplasmic side of the pore (for review see Ref. 11). The two other factors identified in the in vitro transport system as essential components of the nuclear import machinery are the GTP-binding protein Ran/TC4 (herein referred to as Ran (12, 13)) and a small protein of 10 kDa, p10/NTF2. The latter can interact with NPC proteins, Ran, and importin ␤ and appears to be involved in the formation of a pentameric complex including p10, Ran in its GDP-bound form, the two NLS receptor subunits and a nuclear pore protein (14, 15).R...

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Section: Discussionmentioning

confidence: 99%

The Acidic C-terminal Domain of rna1p Is Required for the Binding of Ran·GTP and for RanGAP Activity

Haberland¹,

Becker²,

Gerke³

1997

Journal of Biological Chemistry

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“…SUMO-1 modulates the interaction of the target protein with other cellular proteins and often results in changing the protein's location [9,27,43]. For example, a SUMO-attached protein may be transported to the nucleus [27,39]. Furthermore, there exist functional differences between SUMO-1, SUMO-2 and SUMO-3, such that a greater abundance of SUMO-2 and SUMO-3 acts as a stress response compared with SUMO-1 [48].…”

Section: Upregulation Of Ubiquitin and Sumo Gene Families In The Pfc mentioning

confidence: 99%

Nicotine coregulates multiple pathways involved in protein modification/degradation in rat brain

Kane

Konu

Jennie

et al. 2004

Molecular Brain Research

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Previously, we used cDNA microarrays to demonstrate that the phosphatidylinositol and MAP kinase signaling pathways are regulated by nicotine in different rat brain regions. In the present report, we show that, after exposure to nicotine for 14 days, ubiquitin, ubiquitinconjugating enzymes, 20S and 19S proteasomal subunits, and chaperonin-containing TCP-1 protein (CCT) complex members are upregulated in rat prefrontal cortex (PFC) while being downregulated in the medial basal hypothalamus (MBH). In particular, relative to saline controls, ubiquitins B and C were upregulated by 33% and 47% ( Pb0.01), respectively, in the PFC. The proteasome beta subunit 1 (PSMB1) and 26S ATPase 3 (PSMC3) genes were upregulated in the PFC by 95% and 119% ( Pb0.001), respectively. In addition to the protein degradation pathway of the ubiquitin-proteasome complexes, we observed in the PFC an increase in the expression of small, ubiquitin-related modifiers (SUMO) 1 and 2 by 80% and 33%, respectively ( Pb0.001), and in 3 of 6 CCT subunits by up to 150% ( Pb0.0001). To a lesser extent, a change in the opposite direction was obtained in the expression of the same gene families in the MBH. Quantitative real-time RT-PCR was used to validate the microarray results obtained with some representative genes involved in these pathways. Taken together, our results suggest that, in response to systemic nicotine administration, the ubiquitin-proteasome, SUMO, and chaperonin complexes provide an intricate control mechanism to maintain cellular homeostasis, possibly by regulating the composition and signaling of target neurons in a region-specific manner. D

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“…Its nucleotide-bound state is regulated by the Ran-specific GTPase-activating protein, RanGAP1 [23], and the specific guanine nucleotide exchange factor, RCC1 [24,25]. RanGAP1 is cytoplasmic or attached to the cytoplasmic margin of NPCs after conjugation with a ubiquitin-like protein [26][27][28], whereas RCC1 is exclusively nuclear and bound to chromatin [25,29]. The asymmetric subcellular distribution of the both Ran regulators is thought to result in a high concentration of RanGTP in nucleus, but low in cytoplasm.…”

Section: Introductionmentioning

confidence: 99%

Reduction of exportin 6 activity leads to actin accumulation via failure of RanGTP restoration and NTF2 sequestration in the nuclei of senescent cells

Park¹,

Park²,

Lim³

2011

Experimental Cell Research

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A Small Ubiquitin-Related Polypeptide Involved in Targeting RanGAP1 to Nuclear Pore Complex Protein RanBP2

Cited by 1,152 publications

References 43 publications

The Acidic C-terminal Domain of rna1p Is Required for the Binding of Ran·GTP and for RanGAP Activity

The Acidic C-terminal Domain of rna1p Is Required for the Binding of Ran·GTP and for RanGAP Activity

Nicotine coregulates multiple pathways involved in protein modification/degradation in rat brain

Reduction of exportin 6 activity leads to actin accumulation via failure of RanGTP restoration and NTF2 sequestration in the nuclei of senescent cells

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