1. Biochemistry and Chemical Biology
  2. Structural Biology and Molecular Biophysics

Structural determinants of nuclear export signal orientation in binding CRM1

  1. Ho Yee Joyce Fung
  2. Szu-chin Fu
  3. Chad A Brautigam
  4. Yuh Min Chook  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
https://doi.org/10.7554/eLife.10034
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  1. Ho Yee Joyce Fung
  2. Szu-chin Fu
  3. Chad A Brautigam
  4. Yuh Min Chook
(2015)
Structural determinants of nuclear export signal orientation in binding CRM1
eLife 4:e10034.
https://doi.org/10.7554/eLife.10034
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Abstract

The Chromosome Region of Maintenance 1 (CRM1) protein mediates nuclear export of hundreds of proteins through recognition of their nuclear export signals (NESs), which are highly variable in sequence and structure. The plasticity of the CRM1-NES interaction is not well understood, as there are many NES sequences that seem incompatible with structures of the NES-bound CRM1 groove. Crystal structures of CRM1 bound to two different NESs with unusual sequences showed the NES peptides binding the CRM1 groove in the opposite orientation (minus) to that of previously studied NESs (plus). Comparison of minus and plus NESs identified structural and sequence determinants for NES orientation. The binding of NESs to CRM1 in both orientations results in a large expansion in NES consensus patterns and therefore a corresponding expansion of potential NESs in the proteome.

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Author details

  1. Ho Yee Joyce Fung

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Szu-chin Fu

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Chad A Brautigam

    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Yuh Min Chook

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    yuhmin.chook@utsouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.

Copyright

© 2015, Fung et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Ho Yee Joyce Fung
  2. Szu-chin Fu
  3. Chad A Brautigam
  4. Yuh Min Chook
(2015)
Structural determinants of nuclear export signal orientation in binding CRM1
eLife 4:e10034.
https://doi.org/10.7554/eLife.10034

Share this article

https://doi.org/10.7554/eLife.10034

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Further reading

    1. Structural Biology and Molecular Biophysics

    Nuclear export receptor CRM1 recognizes diverse conformations in nuclear export signals

    Ho Yee Joyce Fung, Szu-Chin Fu, Yuh Min Chook
    Research Advance Updated

    Nuclear export receptor CRM1 binds highly variable nuclear export signals (NESs) in hundreds of different cargoes. Previously we have shown that CRM1 binds NESs in both polypeptide orientations (Fung et al., 2015). Here, we show crystal structures of CRM1 bound to eight additional NESs which reveal diverse conformations that range from loop-like to all-helix, which occupy different extents of the invariant NES-binding groove. Analysis of all NES structures show 5-6 distinct backbone conformations where the only conserved secondary structural element is one turn of helix that binds the central portion of the CRM1 groove. All NESs also participate in main chain hydrogen bonding with human CRM1 Lys568 side chain, which acts as a specificity filter that prevents binding of non-NES peptides. The large conformational range of NES backbones explains the lack of a fixed pattern for its 3-5 hydrophobic anchor residues, which in turn explains the large array of peptide sequences that can function as NESs.