3tj3 | pdb_00003tj3
Structure of importin a5 bound to the N-terminus of Nup50
Structural highlights
Function[IMA1_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. [NUP50_HUMAN] Component of the nuclear pore complex that has a direct role in nuclear protein import. Actively displaces NLSs from importin-alpha, and facilitates disassembly of the importin-alpha:beta-cargo complex and importin recycling. Interacts with multiple transport receptor proteins including CDKN1B. This interaction is required for correct intracellular transport and degradation of CDKN1B.[1] Publication Abstract from PubMedThe human genome encodes six isoforms of importin alpha that show greater than 60% sequence similarity and remarkable substrate specificity. The isoform importin alpha5 can bind phosphorylated cargos such as STAT1 and Epstein-Barr Virus Nuclear Antigen 1, as well as the influenza virus polymerase subunit PB2. In this work, we have studied the interaction of the nucleoporin Nup50 with importin alpha5. We show that the first 47 residues of Nup50 bind to the C terminus of importin alpha5 like a "clip," stabilizing the closed conformation of ARM 10. In vitro, Nup50 binds with high affinity either to empty importin alpha5 or to a preassembled complex of importin alpha5 bound to the C-terminal domain of the import cargo PB2, resulting in a trimeric complex. By contrast, PB2 can only bind with high affinity to importin alpha5 in the absence of Nup50. This suggests that Nup50 primary function may not be to actively displace the import cargo from importin alpha5 but rather to prevent cargo rebinding in preparation for recycling. This is the first evidence for a nucleoporin modulating the import reaction by directly altering the three-dimensional structure of an import adaptor. Nucleoporin Nup50 stabilizes closed conformation of armadillo repeat 10 in importin alpha5.,Pumroy RA, Nardozzi JD, Hart DJ, Root MJ, Cingolani G J Biol Chem. 2012 Jan 13;287(3):2022-31. doi: 10.1074/jbc.M111.315838. Epub 2011 , Nov 30. PMID:22130666[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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