Differential recognition of canonical NF-κB dimers by Importin α3

Tyler J. Florio, Ravi K. Lokareddy, Daniel P. Yeggoni, Rajeshwer S. Sankhala, Connor A. Ott, Richard E. Gillilan and Gino Cingolani ()
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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

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-28846-z

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