Structural Determinants and Mechanism of Mammalian CRM1 Allostery

Dölker, Nicole; Blanchet, Clément E.; Voß, Béla; Haselbach, David; Kappel, Christian; Monecke, Thomas; Svergun, Dmitri I.; Stark, Holger; Ficner, Ralf; Zachariae, Ulrich; Grubmüller, Helmut; Dickmanns, Achim

doi:10.1016/j.str.2013.05.015

Cited by 20 publications

(45 citation statements)

References 44 publications

(65 reference statements)

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“…3B). Molecular dynamics simulations suggested that H9 loop interactions are important for maintaining rigidity of the CRM1 ring [91]. …”

Section: A Summary Of Crm1 Structuresmentioning

confidence: 99%

“…4D to the open groove in Fig. 3D) [91]. Two other structural features are clearly different in the unliganded state.…”

Section: A Summary Of Crm1 Structuresmentioning

confidence: 99%

“…The loop interacts with helices H11B and H12B, which rotated to bring helices H11A and H12A closer to achieve NES groove closure [95, 96]. Results from molecular dynamics simulations and mutagenesis of the H9 loop support the notion that H9 loop-NES groove interactions are key in controlling the opening and closing of the groove [91, 98]. Second, the C-terminal helix H21B (also known as the C-extension) of unliganded CRM1 crosses the CRM1 ring in a conformation similar to that seen in the binary CRM1-SNUPN complex (Fig.…”

Section: A Summary Of Crm1 Structuresmentioning

confidence: 99%

“…Their molecular dynamics simulations suggested that CRM1 ring compaction, which also corresponds with an open NES groove, is the main factor that determines CRM1 activity. EM and SAXS analysis of full length CRM1 revealed intrinsic flexibility of the CRM1 ring, which samples both extended and compact conformations [91, 96]. Normal mode analysis of C-terminally truncated human CRM1 showed increased CRM1 flexibility with the NES groove fluctuating to various widths, suggesting that the C-terminal helix is important in controlling conformation flexibility of CRM1 [96, 97].…”

Section: A Summary Of Crm1 Structuresmentioning

confidence: 99%

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Atomic basis of CRM1-cargo recognition, release and inhibition

Fung

Chook

2014

Seminars in Cancer Biology

135

124

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CRM1 or XPO1 is the major nuclear export receptor in the cell, which controls the nuclear-cytoplasmic localization of many proteins and RNAs. CRM1 is also a promising cancer drug target as the transport receptor is overexpressed in many cancers and quite a few of its cargos are misregulated in the diseases and hence mislocalized to the cytoplasm. Atomic level understanding of CRM1 function has greatly facilitated recent drug discovery and development of CRM1 inhibitors to target a variety of malignancies. Numerous atomic resolution CRM1 structures are now available, explaining how the exporter recognizes nuclear export signals in its cargos, how RanGTP and cargo bind with positive cooperativity, how RanBP1 causes release of export cargos in the cytoplasm and how diverse inhibitors such as Leptomycin B and the new KPT-SINE compounds block nuclear export. This review summarizes the structure-function studies that explain CRM1-cargo recognition, release and inhibition.

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“…3B). Molecular dynamics simulations suggested that H9 loop interactions are important for maintaining rigidity of the CRM1 ring [91]. …”

Section: A Summary Of Crm1 Structuresmentioning

confidence: 99%

“…4D to the open groove in Fig. 3D) [91]. Two other structural features are clearly different in the unliganded state.…”

Section: A Summary Of Crm1 Structuresmentioning

confidence: 99%

Section: A Summary Of Crm1 Structuresmentioning

confidence: 99%

Section: A Summary Of Crm1 Structuresmentioning

confidence: 99%

See 2 more Smart Citations

Atomic basis of CRM1-cargo recognition, release and inhibition

Fung

Chook

2014

Seminars in Cancer Biology

135

124

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“…These parameters were previously used for simulations of a-solenoid proteins and were shown to give reliable results (31,32,48,49).…”

Section: Simulationsmentioning

confidence: 99%

MD Simulations and FRET Reveal an Environment-Sensitive Conformational Plasticity of Importin-β

Halder

Dölker

Van

et al. 2015

Biophysical Journal

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The nuclear pore complex mediates nucleocytoplasmic transport of macromolecules in eukaryotic cells. Transport through the pore is restricted by a hydrophobic selectivity filter comprising disordered phenylalanine-glycine-rich repeats of nuclear pore proteins. Exchange through the pore requires specialized transport receptors, called exportins and importins, that interact with cargo proteins in a RanGTP-dependent manner. These receptors are highly flexible superhelical structures composed of HEAT-repeat motifs that adopt various degrees of extension in crystal structures. Here, we performed molecular-dynamics simulations using crystal structures of Importin-β in its free form or in complex with nuclear localization signal peptides as the starting conformation. Our simulations predicted that initially compact structures would adopt extended conformations in hydrophilic buffers, while contracted conformations would dominate in more hydrophobic solutions, mimicking the environment of the nuclear pore. We confirmed this experimentally by Förster resonance energy transfer experiments using dual-fluorophore-labeled Importin-β. These observations explain seemingly contradictory crystal structures and suggest a possible mechanism for cargo protection during passage of the nuclear pore. Such hydrophobic switching may be a general principle for environmental control of protein function.

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A structurally plastic ribonucleoprotein complex mediates post‐transcriptional gene regulation in HIV‐1

2016

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HIV replication requires the nuclear export of essential, intron-containing viral RNAs. To facilitate export, HIV encodes the viral accessory protein Rev which binds unspliced and partially spliced viral RNAs and creates a ribonucleoprotein complex that recruits the cellular Chromosome maintenance factor 1 export machinery. Exporting RNAs in this manner bypasses the necessity for complete splicing as a prerequisite for mRNA export, and allows intron-containing RNAs to reach the cytoplasm intact for translation and virus packaging. Recent structural studies have revealed that this entire complex exhibits remarkable plasticity at many levels of organization, including RNA folding, protein–RNA recognition, multimer formation, and host factor recruitment. In this review, we explore each aspect of plasticity from structural, functional, and possible therapeutic viewpoints.

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Structural Determinants and Mechanism of Mammalian CRM1 Allostery

Cited by 20 publications

References 44 publications

Atomic basis of CRM1-cargo recognition, release and inhibition

Atomic basis of CRM1-cargo recognition, release and inhibition

MD Simulations and FRET Reveal an Environment-Sensitive Conformational Plasticity of Importin-β

A structurally plastic ribonucleoprotein complex mediates post‐transcriptional gene regulation in HIV‐1

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