7leu
From Proteopedia
Structure of importin a2 bound to p65-NLS
Structural highlights
FunctionIMA1_MOUSE Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1. Binds specifically and directly to substrates containing either a simple or bipartite NLS motif. Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Publication Abstract from PubMedNuclear translocation of the p50/p65 heterodimer is essential for NF-kappaB signaling. In unstimulated cells, p50/p65 is retained by the inhibitor IkappaBalpha in the cytoplasm that masks the p65-nuclear localization sequence (NLS). Upon activation, p50/p65 is translocated into the nucleus by the adapter importin alpha3 and the receptor importin beta. Here, we describe a bipartite NLS in p50/p65, analogous to nucleoplasmin NLS but exposed in trans. Importin alpha3 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 alpha3 that stabilizes a helical conformation of the p65-NLS. Neither conformational change was observed for importin alpha1, which makes fewer bonds with the p50/p65 NLSs, explaining the preference for alpha3. We propose that importin alpha3 discriminates between the transcriptionally active p50/p65 heterodimer and p50/p50 and p65/65 homodimers, ensuring fidelity in NF-kappaB signaling. Differential recognition of canonical NF-kappaB dimers by Importin alpha3.,Florio TJ, Lokareddy RK, Yeggoni DP, Sankhala RS, Ott CA, Gillilan RE, Cingolani G Nat Commun. 2022 Mar 8;13(1):1207. doi: 10.1038/s41467-022-28846-z. PMID:35260573[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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