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Journal Article

MD simulations and FRET reveal an environment: Sensitive conformational plasticity of Importin-beta.

MPS-Authors
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Dölker,  N.
Department of Theoretical and Computational Biophysics, MPI for biophysical chemistry, Max Planck Society;

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Grubmüller,  H.
Department of Theoretical and Computational Biophysics, MPI for biophysical chemistry, Max Planck Society;

Fulltext (public)

2179820.pdf
(Publisher version), 2MB

Supplementary Material (public)

2179820_Suppl_1.pdf
(Supplementary material), 3MB

2179820_Suppl_2.pdf
(Supplementary material), 5MB

Citation

Halder, K., Dölker, N., Van, Q., Gregor, I., Dickmanns, A., Baade, I., et al. (2015). MD simulations and FRET reveal an environment: Sensitive conformational plasticity of Importin-beta. Biophysical Journal, 109(2), 277-286. doi:10.1016/j.bpj.2015.06.014.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0028-2A7D-A
Abstract
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-beta 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 Forster resonance energy transfer experiments using dual-fluorophore-labeled Importin-beta. 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.