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Crystal structure of importin-alpha3 bound to the nuclear localization signal of Ran-binding protein 3
Structural highlights
FunctionIMA3_HUMAN 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. In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLS. In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLS. Publication Abstract from PubMedRan-binding protein 3 (RanBP3) is a primarily nuclear Ran-binding protein that functions as an accessory factor in the Ran GTPase system. RanBP3 associates with Ran-specific nucleotide exchange factor RCC1 and enhances its catalytic activity towards Ran. RanBP3 also promotes CRM1-mediated nuclear export as well as CRM1-independent nuclear export of beta-catenin, Smad2, and Smad3. Nuclear import of RanBP3 is dependent on the nuclear import adaptor protein importin-alpha and, RanBP3 is imported more efficiently by importin-alpha3 than by other members of the importin-alpha family. Protein kinase signaling pathways control nucleocytoplasmic transport through phosphorylation of RanBP3 at Ser58, immediately C-terminal to the nuclear localization signal (NLS) in the N-terminal region of RanBP3. Here we report the crystal structure of human importin-alpha3 bound to an N-terminal fragment of human RanBP3 containing the NLS sequence that is necessary and sufficient for nuclear import. The structure reveals that RanBP3 binds to importin-alpha3 residues that are strictly conserved in all seven isoforms of human importin-alpha at the major NLS-binding site, indicating that the region of importin-alpha outside the NLS-binding site, possibly the autoinhibotory importin-beta1-binding domain, may be the key determinant for the preferential binding of RanBP3 to importin-alpha3. Computational docking simulation indicates that phosphorylation of RanBP3 at Ser58 could potentially stabilize the association of RanBP3 with importin-alpha through interactions between the phosphate moiety of phospho-Ser58 of RanBP3 and a cluster of basic residues (Arg96 and Lys97 in importin-alpha3) on armadillo repeat 1 of importin-alpha. Crystal structure of importin-alpha3 bound to the nuclear localization signal of Ran-binding protein 3.,Koyama M, Matsuura Y Biochem Biophys Res Commun. 2017 Sep 23;491(3):609-613. doi:, 10.1016/j.bbrc.2017.07.155. Epub 2017 Jul 29. PMID:28760339[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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