The Structure of the Nuclear Export Receptor Cse1 in Its Cytosolic State Reveals a Closed Conformation Incompatible with Cargo Binding

Cook, Atlanta G.; Fernández, Elena Fernández; Lindner, Doris; Ebert, J.; Schlenstedt, Gabriel; Conti, Elena

doi:10.1016/j.molcel.2005.03.021

Cited by 74 publications

(86 citation statements)

References 30 publications

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“…They found that, mainly driven by electrostatic interactions, the structure of Cse1p spontaneously collapses and adopts a conformation close to the experimentally determined cytoplasmic form within a relatively short timescale of 10 ns. Simulations of mutants with different electrostatic surface potentials did not reveal a significant conformational change but remained in an open conformation which is in good agreement with experimental findings (Cook et al 2005). This example shows that functionally relevant conformational changes that occur on short time scales can be studied by MD simulations.…”

Section: Nuclear Transport Receptorssupporting

confidence: 88%

Protein Dynamics: From Structure to Function

Kubitzki

Groot

Seeliger

2009

From Protein Structure to Function With Bioinformatics

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Understanding protein function requires detailed knowledge about protein dynamics, i.e. the different conformational states the system can adopt. Despite substantial experimental progress, simulation techniques such as molecular dynamics (MD) currently provide the only routine means to obtain dynamical information at an atomic level on timescales of nano-to microseconds. Even with the current development of computational power, sampling techniques beyond MD are necessary to enhance conformational sampling of large proteins and assemblies thereof. The use of collective coordinates has proven to be a promising means in this respect, either as a tool for analysis or as part of new sampling algorithms. Starting from MD simulations, several enhanced sampling algorithms for biomolecular simulations are reviewed in this chapter. Examples are given throughout illustrating how consideration of the dynamic properties of a protein sheds light on its function. Molecular Dynamics SimulationsOver the last decades, experimental techniques have made substantial progress in revealing the three-dimensional structure of proteins, in particular X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy and cryo-electron microscopy. Going beyond the static picture of single protein structures has proven to be more challenging, although, a number of techniques such as NMR relaxation, fluorescence spectroscopy or time-resolved X-ray crystallography have emerged

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Section: Nuclear Transport Receptorssupporting

confidence: 88%

Protein Dynamics: From Structure to Function

Kubitzki

Groot

Seeliger

2009

From Protein Structure to Function With Bioinformatics

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“…This region is potentially solvent exposed and is close to the region that undergoes a major conformational change on binding of cargo. 29 Interestingly, in addition to CAS, we also detected an interaction between the SID and the N-terminal 165 amino acids of NUP93 (Fig. 1A), which localises to the nuclear basket of the nuclear pore complex.…”

Section: Discussionmentioning

confidence: 80%

Functional Interaction of CREB Binding Protein (CBP) with Nuclear Transport Proteins and Modulation by HDAC Inhibitors

Ryan

Harries²,

Kindle³

et al. 2006

Cell Cycle

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Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=3207 KEY WORDSCBP, CAS/CSE1p, importin, NUP93, HDAC inhibitor, acetyltransferase ACKNOWLEDGEMENTS Report Functional Interaction of CREB Binding Protein (CBP) with Nuclear Transport Proteins and Modulation by HDAC Inhibitors ABSTRACTNuclear transport proteins such as CSE1, NUP93 and Importin-α have recently been shown to be chromatin-associated proteins in yeast, which have unexpected functions in gene regulation. Here we report interactions between the mammalian histone acetyltransferase CBP with nuclear transport proteins CAS (a CSE1 homologue) and Importin-α (Impα) and NUP93. CAS was found to bind the SRC1 interaction domain (SID) of CBP via a leucine-rich motif in the N-terminus of the protein, that is conserved in other SID-binding proteins. Coimmunoprecipitation experiments also revealed that CBP and Impα proteins form a complex. As Impα is a known acetylation target of CBP/p300, and is recycled to the cytoplasm via the exportin CAS, we investigated whether HDAC inhibitors would alter the subcellular localization of these proteins. Treatment of COS-1 cells with the HDAC inhibitors trichostatin A or sodium butyrate resulted in sequestration of Impα in the nuclear envelope, accumulation of CAS in nuclear aggregates, and an increased number of CBP-containing PML bodies per cell. In addition, HDACi treatment appeared to enhance the association of Impα and CBP in coimmunoprecipitation experiments. Our results provide evidence for novel functional interactions between the chromatin modification enzyme CBP and nuclear transport proteins in mammalian cells.

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“…In contrast to the fact that Exp5 undergoes a transition to an extended state after dissociation of its binding partners, the exportin CAS/Cse1p is more compact in the unbound state than in the ternary export complex. It is suggested that the presence of an intra-molecular interaction, which constrains the karyopherin superhelix in a tight ring-shape structure, seals off the cargo-binding sites, keeping cargo from rebinding to CAS/Cse1p in the cytosol (Cook et al 2005;Zachariae and Grubmüller 2006).…”

Section: Discussionmentioning

confidence: 99%

Dynamic mechanisms for pre-miRNA binding and export by Exportin-5

Wang¹,

Xue²,

Zhi³

et al. 2011

RNA

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The biogenesis and function of mature microRNAs (miRNAs) is dependent on the nuclear export of miRNA precursors (premiRNA) by . To characterize the molecular mechanisms of how pre-miRNA is recognized and transported by Exp5, we have performed 21 molecular dynamic (MD) simulations of RNA-bound Exp5 (Exp5-RanGTP-premiRNA, Exp5-RanGDP-premiRNA, Exp5-premiRNA), RNA-unbound Exp5 (Exp5-RanGTP, Exp5-RanGDP, apo-Exp5), and pre-miRNA. Our simulations with standard MD, steered molecular dynamics (SMD), and energy analysis have shown that (1) Free Exp5 undergoes extensive opening motion, and in this way facilitates the RanGTP binding. (2) RanGTP efficiently regulates the association/dissociation of pre-miRNA to its complex by inducing conformational changes in the HEAT-repeat helix stacking of Exp5. (3) The GTP hydrolysis prevents Ran from rebinding to Exp5 by regulating the hydrophobic interfaces and salt bridges between Ran and Exp5. (4) The transition from the A9-form to the A-form of the pre-miRNA modulates the structural complementarities between the protein and the pre-miRNA, thus promoting efficient assembly of the complex. (5) The baseflipping process (from the closed to the fully flipped state) of the 2-nt 39 overhang is a prerequisite for the pre-miRNA recognition by Exp5, which occurs in a sequence-independent manner as evidenced by the fact that different 2-nt 39 overhangs bind to Exp5 in essentially the same way. And finally, a plausible mechanism of the pre-miRNA export cycle has been proposed explaining how the protein-protein and protein-RNA interactions are coordinated in physiological conditions.

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The Structure of the Nuclear Export Receptor Cse1 in Its Cytosolic State Reveals a Closed Conformation Incompatible with Cargo Binding

Cited by 74 publications

References 30 publications

Protein Dynamics: From Structure to Function

Protein Dynamics: From Structure to Function

Functional Interaction of CREB Binding Protein (CBP) with Nuclear Transport Proteins and Modulation by HDAC Inhibitors

Dynamic mechanisms for pre-miRNA binding and export by Exportin-5

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