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Three-dimensional context rather than NLS amino acid sequence determines importin α subtype specificity for RCC1

Author

Listed:
  • Rajeshwer S. Sankhala

    (Thomas Jefferson University)

  • Ravi K. Lokareddy

    (Thomas Jefferson University)

  • Salma Begum

    (Thomas Jefferson University)

  • Ruth A. Pumroy

    (Thomas Jefferson University
    University of Utah)

  • Richard E. Gillilan

    (Cornell University)

  • Gino Cingolani

    (Thomas Jefferson University
    National Research Council)

Abstract

Active nuclear import of Ran exchange factor RCC1 is mediated by importin α3. This pathway is essential to generate a gradient of RanGTP on chromatin that directs nucleocytoplasmic transport, mitotic spindle assembly and nuclear envelope formation. Here we identify the mechanisms of importin α3 selectivity for RCC1. We find this isoform binds RCC1 with one order of magnitude higher affinity than the generic importin α1, although the two isoforms share an identical NLS-binding groove. Importin α3 uses its greater conformational flexibility to wedge the RCC1 β-propeller flanking the NLS against its lateral surface, preventing steric clashes with its Armadillo-core. Removing the β-propeller, or inserting a linker between NLS and β-propeller, disrupts specificity for importin α3, demonstrating the structural context rather than NLS sequence determines selectivity for isoform 3. We propose importin α3 evolved to recognize topologically complex NLSs that lie next to bulky domains or are masked by quaternary structures.

Suggested Citation

  • Rajeshwer S. Sankhala & Ravi K. Lokareddy & Salma Begum & Ruth A. Pumroy & Richard E. Gillilan & Gino Cingolani, 2017. "Three-dimensional context rather than NLS amino acid sequence determines importin α subtype specificity for RCC1," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-01057-7
    DOI: 10.1038/s41467-017-01057-7
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    Cited by:

    1. Thilini S. Munasinghe & Megan R. Edwards & Sofiya Tsimbalyuk & Olivia A. Vogel & Kate M. Smith & Murray Stewart & Justin K. Foster & Loretta A. Bosence & David Aragão & Justin A. Roby & Christopher F., 2022. "MERS-CoV ORF4b employs an unusual binding mechanism to target IMPα and block innate immunity," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    2. Tyler J. Florio & Ravi K. Lokareddy & Daniel P. Yeggoni & Rajeshwer S. Sankhala & Connor A. Ott & Richard E. Gillilan & Gino Cingolani, 2022. "Differential recognition of canonical NF-κB dimers by Importin α3," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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