Architecture of CRM1/Exportin1 Suggests How Cooperativity Is Achieved during Formation of a Nuclear Export Complex

Petosa, Carlo; Schoehn, Guy; Askjaer, Peter; Bauer, Ulrike; Moulin, Martine; Steuerwald, Ulrich; Soler-López, Montserrat; Baudin, Florence; Mattaj, Iain W.; Müller, Christoph W.

doi:10.1016/j.molcel.2004.11.018

Cited by 138 publications

(139 citation statements)

References 52 publications

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“…1(a) (dark rectangles). This agrees with reports describing members of the importin-b superfamily to contain multiple HEAT repeats (Petosa et al, 2004).…”

Section: Resultssupporting

confidence: 93%

KapI, a non-essential member of the Pse1p/Imp5 karyopherin family, controls colonial and asexual development in Aspergillus nidulans

Etxebeste

Markina-Iñarrairaegui

Garzia

et al. 2009

Microbiology

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Asexual development in the filamentous fungus Aspergillus nidulans is governed by the timely expression and cellular localization of multiple transcription factors. Hence, factors mediating import and export across the nuclear pore complexes (karyopherins) are expected to play a key role in coordinating the developmental programme. Here we characterize KapI, a putative homologue of the Saccharomyces cerevisiae Kap121/Pse1p karyopherin. KapI is a non-essential importin-b-like protein located in the nucleus during vegetative growth and conidiophore development. The DkapI phenotype is aconidial with many aerial hyphae. This phenotype can be suppressed under abiotic stress. In this regard, it resembles that of the null allele of the bZIP transcription factor FlbB. However a DflbB; DkapI double mutant exhibited an additive phenotype with totally impaired conidiation, unresponsive to abiotic stress. In contrast to DflbB, the null kapI mutant is not a fluffy-low-bristle expression mutant. Taken together the findings indicate that KapI is required during asexual development, mediating the nuclear transport of factors acting in a different pathway(s) from those involving the upstream developmental activators.

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“…1(a) (dark rectangles). This agrees with reports describing members of the importin-b superfamily to contain multiple HEAT repeats (Petosa et al, 2004).…”

Section: Resultssupporting

confidence: 93%

KapI, a non-essential member of the Pse1p/Imp5 karyopherin family, controls colonial and asexual development in Aspergillus nidulans

Etxebeste

Markina-Iñarrairaegui

Garzia

et al. 2009

Microbiology

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“…1A). As in Imp13 and some other β-karyopherins (37,42), the C-terminal HEAT repeat of Tnpo3 is expanded by an additional α-helix. Unliganded Tnpo3 crystallized in the triclinic space group P1 with four molecules per unit cell, forming a pair of homodimers composed of interlocking protein chains (Movie S1 and SI Appendix, Fig.…”

Section: Resultsmentioning

confidence: 91%

Structural basis for nuclear import of splicing factors by human Transportin 3

Maertens

Cook

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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167

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Transportin 3 (Tnpo3, Transportin-SR2) is implicated in nuclear import of splicing factors and HIV-1 replication. Herein, we show that the majority of cellular Tnpo3 binding partners contain arginineserine (RS) repeat domains and present crystal structures of human Tnpo3 in its free as well as GTPase Ran-and alternative splicing factor/splicing factor 2 (ASF/SF2)-bound forms. The flexible β-karyopherin fold of Tnpo3 embraces the RNA recognition motif and RS domains of the cargo. A constellation of charged residues on and around the arginine-rich helix of Tnpo3 HEAT repeat 15 engage the phosphorylated RS domain and are critical for the recognition and nuclear import of ASF/SF2. Mutations in the same region of Tnpo3 impair its interaction with the cleavage and polyadenylation specificity factor 6 (CPSF6) and its ability to support HIV-1 replication. Steric incompatibility of the RS domain and RanGTP engagement by Tnpo3 provides the mechanism for cargo release in the nucleus. Our results elucidate the structural bases for nuclear import of splicing factors and the Tnpo3-CPSF6 nexus in HIV-1 biology.T he transport of macromolecules between cytoplasm and nucleus is orchestrated by a family of nuclear import and export receptors (1). Referred to as importins and exportins, these proteins bind their specific cargoes and translocate them across the nuclear pore complex. The process is regulated by the small GTPase Ran that partitions between cytoplasm and nucleus in the predominantly GDP-and GTP-bound form, respectively. Importins associate with their cargoes in the cytoplasm, and the competitive binding of RanGTP induces them to release their cargoes in the nucleus (2). Most nuclear import/export receptors belong to the β-karyopherin family of proteins, with 22 members encoded in the human genome (3). The majority of β-karyopherins bind their cargoes directly, recognizing a linear nuclear localization or export signal and/or a specific tertiary/quaternary structural feature (4, 5).A fundamentally important type of a nuclear localization signal (NLS), comprising sequences rich in Arg-Ser and/or ArgAsp/Glu/Gly dipeptides (referred to as RS or RS-like domains), belongs to the family of Ser/Arg-rich (SR) proteins. These nuclear proteins also contain RNA recognition motif (RRM) domains and play essential roles in pre-mRNA splicing and 3′ processing and participate in transcription regulation, mRNA transport, translation, and nonsense-mediated mRNA decay (6). The splicing factors alternative splicing factor/splicing factor 2 (ASF/SF2) and SC35 along with the cleavage and polyadenylation specificity factor 6 (CPSF6, also known as CF-Im-68) are among the best-characterized metazoan SR proteins (7-10). The SR protein family can be further extended by inclusion of a structurally and functionally diverse group of nuclear proteins that possess RS repeats but lack RRM domains (11). The RS domains are processively phosphorylated on their Ser residues by a set of dedicated kinases (12-16). Phosphorylation of SR proteins is thought to...

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“…Nevertheless, both NESs are required for CPEB1 localization in CNoBs, suggesting the simultaneous binding of one CPEB1 protein to two Crm1 molecules. Although the C-terminal region of Crm1 has been reported to dimerize in solution, there is no evidence that the full-length protein does (Petosa et al, 2004). However, two Crm1 molecules could be brought closer together through interaction with other proteins.…”

Section: Cpeb1 Foci Colocalize With Crm1mentioning

confidence: 99%

“…However, two Crm1 molecules could be brought closer together through interaction with other proteins. Interestingly, CPEB1 dissociated from Crm1 in the nucleoli of cells treated with actinomycin D. At the nuclear envelope, the only mechanism reported for Crm1 cargo release is the hydrolysis of Ran-GTP into Ran-GDP (Petosa et al, 2004). It remains to be assessed whether a similar mechanism can occur in nucleolus, and, in such a case, how it could be sensitive to ongoing RNA polymerase I transcription.…”

Section: Cpeb1 Foci Colocalize With Crm1mentioning

confidence: 99%

Nucleocytoplasmic Traffic of CPEB1 and Accumulation in Crm1 Nucleolar Bodies

Ernoult‐Lange

Wilczynska

Harper

et al. 2009

MBoC

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The translational regulator CPEB1 plays a major role in the control of maternal mRNA in oocytes, as well as of subsynaptic mRNAs in neurons. Although mainly cytoplasmic, we found that CPEB1 protein is continuously shuttling between nucleus and cytoplasm. Its export is controlled by two redundant NES motifs dependent on the nuclear export receptor Crm1. In the nucleus, CPEB1 accumulates in a few foci most often associated with nucleoli. These foci are different from previously identified nuclear bodies. They contain Crm1 and were called Crm1 nucleolar bodies (CNoBs). CNoBs depend on RNA polymerase I activity, indicating a role in ribosome biogenesis. However, although they form in the nucleolus, they never migrate to the nuclear envelope, precluding a role as a mediator for ribosome export. They could rather constitute a platform providing factors for ribosome assembly or export. The behavior of CPEB1 in CNoBs raises the possibility that it is involved in ribosome biogenesis.

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Architecture of CRM1/Exportin1 Suggests How Cooperativity Is Achieved during Formation of a Nuclear Export Complex

Cited by 138 publications

References 52 publications

KapI, a non-essential member of the Pse1p/Imp5 karyopherin family, controls colonial and asexual development in Aspergillus nidulans

KapI, a non-essential member of the Pse1p/Imp5 karyopherin family, controls colonial and asexual development in Aspergillus nidulans

Structural basis for nuclear import of splicing factors by human Transportin 3

Nucleocytoplasmic Traffic of CPEB1 and Accumulation in Crm1 Nucleolar Bodies

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