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Structural basis for leucine-rich nuclear export signal recognition by CRM1

Nature volume 458, pages 1136–1141 (2009)Cite this article

An Erratum to this article was published on 24 September 2009

Abstract

CRM1 (also known as XPO1 and exportin 1) mediates nuclear export of hundreds of proteins through the recognition of the leucine-rich nuclear export signal (LR-NES). Here we present the 2.9 Å structure of CRM1 bound to snurportin 1 (SNUPN). Snurportin 1 binds CRM1 in a bipartite manner by means of an amino-terminal LR-NES and its nucleotide-binding domain. The LR-NES is a combined α-helical-extended structure that occupies a hydrophobic groove between two CRM1 outer helices. The LR-NES interface explains the consensus hydrophobic pattern, preference for intervening electronegative residues and inhibition by leptomycin B. The second nuclear export signal epitope is a basic surface on the snurportin 1 nucleotide-binding domain, which binds an acidic patch on CRM1 adjacent to the LR-NES site. Multipartite recognition of individually weak nuclear export signal epitopes may be common to CRM1 substrates, enhancing CRM1 binding beyond the generally low affinity LR-NES. Similar energetic construction is also used in multipartite nuclear localization signals to provide broad substrate specificity and rapid evolution in nuclear transport.

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Figure 1: Overall structure of the CRM1–SNUPN complex.
Figure 2: The LR-NES-binding site.
Figure 3: Hydrophobic residues are critical for LR-NES recognition.
Figure 4: Localization of the SNUPN and its LR-NES in yeast.
Figure 5: Interactions of CRM1 with the SNUPN NES epitope II.

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Protein Data Bank

Data deposits

Atomic coordinates and structure factors have been deposited in the Protein Data Bank under accession codes rcsb051649 and 3GB8.

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Acknowledgements

We thank Y. Sheng, C. Kong, D. Tomchick and C. Dann for assistance during data collection and structure determination, S. Padrick for advice on fluorescence binding assays, G. Süel and T. Cagatay for help with microscopy, K. Weis for yeast strains and constructs, X. Zhang, L. Rice and M. Rosen for discussion. This work is funded by National Institute of Health (NIH) grants R01GM069909, R01GM069909-03S1, 5-T32-GM008297, Welch Foundation grant I-1532 and the UT Southwestern Endowed Scholars Program. Use of the Argonne National Laboratory Stuctural Biology Center beamlines at the Advanced Photon Source, was supported by the US Department of Energy, Office of Energy Research, under contract no. W-31-109-ENG-38.

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Authors and Affiliations

  1. Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park, Dallas, Texas 75390-9041, USA,

    Xiuhua Dong, Anindita Biswas, Katherine E. Süel, Laurie K. Jackson, Rita Martinez, Hongmei Gu & Yuh Min Chook

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Correspondence to Yuh Min Chook.

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Dong, X., Biswas, A., Süel, K. et al. Structural basis for leucine-rich nuclear export signal recognition by CRM1. Nature 458, 1136–1141 (2009). https://doi.org/10.1038/nature07975

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