Differential recognition of canonical NF-κB dimers by Importin α3

Nuclear translocation of the p50/p65 heterodimer is essential for NF-kappa B signaling. Here, the authors identify a bipartite Nuclear Localization Signal in the NF-kappa B p50/p65 heterodimer that is recognized with high affinity by importin alpha 3. Nuclear translocation of the p50/p65 heterodimer is essential for NF-kappa B signaling. In unstimulated cells, p50/p65 is retained by the inhibitor I kappa B alpha in the cytoplasm that masks the p65-nuclear localization sequence (NLS). Upon activation, p50/p65 is translocated into the nucleus by the adapter importin alpha 3 and the receptor importin beta. Here, we describe a bipartite NLS in p50/p65, analogous to nucleoplasmin NLS but exposed in trans. Importin alpha 3 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 alpha 3 that stabilizes a helical conformation of the p65-NLS. Neither conformational change was observed for importin alpha 1, which makes fewer bonds with the p50/p65 NLSs, explaining the preference for alpha 3. We propose that importin alpha 3 discriminates between the transcriptionally active p50/p65 heterodimer and p50/p50 and p65/65 homodimers, ensuring fidelity in NF-kappa B signaling.

Automated summary

The authors identify a bipartite Nuclear Localization Signal in the NF-kappa B p50/p65 heterodimer that is recognized with high affinity by importin alpha 3. This study reveals the specific structure and mechanism of this signal and highlights the important role of importin alpha 3 in NF-kappa B signaling.