Document Type
Article
Publication Date
3-8-2022
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.
Recommended Citation
Florio, Tyler J.; Lokareddy, Ravi K; Yeggoni, Daniel P; Sankhala, Rajeshwer S; Ott, Connor A; Gillilan, Richard E; and Cingolani, Gino, "Differential recognition of canonical NF-κB dimers by Importin α3" (2022). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 209.
https://jdc.jefferson.edu/bmpfp/209
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
35260573
Language
English
Comments
This article is the author’s final published version in Nature Communications, Volume 13, Issue 1, March 2022, Article number 1207.
The published version is available at https://doi.org/10.1038/s41467-022-28846-z. Copyright © Florio et al.