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Differential recognition of canonical NF-κB dimers by Importin α3

Author

Listed:
  • Tyler J. Florio

    (Thomas Jefferson University)

  • Ravi K. Lokareddy

    (Thomas Jefferson University)

  • Daniel P. Yeggoni

    (Thomas Jefferson University)

  • Rajeshwer S. Sankhala

    (Walter Reed Army Institute of Research)

  • Connor A. Ott

    (Thomas Jefferson University)

  • Richard E. Gillilan

    (Cornell University)

  • Gino Cingolani

    (Thomas Jefferson University)

Abstract

Nuclear translocation of the p50/p65 heterodimer is essential for NF-κB signaling. In unstimulated cells, p50/p65 is retained by the inhibitor IκBα in the cytoplasm that masks the p65-nuclear localization sequence (NLS). Upon activation, p50/p65 is translocated into the nucleus by the adapter importin α3 and the receptor importin β. Here, we describe a bipartite NLS in p50/p65, analogous to nucleoplasmin NLS but exposed in trans. Importin α3 accommodates the p50- and p65-NLSs at the major and minor NLS-binding pockets, respectively. The p50-NLS is the predominant binding determinant, while the p65-NLS induces a conformational change in the Armadillo 7 of importin α3 that stabilizes a helical conformation of the p65-NLS. Neither conformational change was observed for importin α1, which makes fewer bonds with the p50/p65 NLSs, explaining the preference for α3. We propose that importin α3 discriminates between the transcriptionally active p50/p65 heterodimer and p50/p50 and p65/65 homodimers, ensuring fidelity in NF-κB signaling.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28846-z
    DOI: 10.1038/s41467-022-28846-z
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    References listed on IDEAS

    as
    1. 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.
    2. Bikshapathi Jagga & Megan Edwards & Miriam Pagin & Kylie M. Wagstaff & David Aragão & Noelia Roman & Jeffrey D. Nanson & Shane R. Raidal & Nicole Dominado & Murray Stewart & David A. Jans & Gary R. Hi, 2021. "Structural basis for nuclear import selectivity of pioneer transcription factor SOX2," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    3. Kate M. Smith & Sofiya Tsimbalyuk & Megan R. Edwards & Emily M. Cross & Jyoti Batra & Tatiana P. Soares da Costa & David Aragão & Christopher F. Basler & Jade K. Forwood, 2018. "Structural basis for importin alpha 3 specificity of W proteins in Hendra and Nipah viruses," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    4. Frances E. Chen & De-Bin Huang & Yong-Qing Chen & Gourisankar Ghosh, 1998. "Crystal structure of p50/p65 heterodimer of transcription factor NF-κB bound to DNA," Nature, Nature, vol. 391(6665), pages 410-413, January.
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