4b18
From Proteopedia
The crystal structure of human Importin alpha 5 with TERT NLS peptide
Structural highlights
FunctionIMA5_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. Publication Abstract from PubMedTelomeres are essential for chromosome integrity and protection, and their maintenance requires the ribonucleoprotein enzyme telomerase. Previously, we have shown that human telomerase reverse transcriptase (hTERT) contains a bipartite nuclear localization signal (NLS; residues 222-240) that is responsible for nuclear import, and that Akt-mediated phosphorylation of residue S227 is important for efficient nuclear import of hTERT. Here, we show that hTERT binds to importin-alpha proteins through the bipartite NLS and that this heterodimer then forms a complex with importin-beta proteins to interact with the nuclear pore complex. Depletion of individual importin-alpha proteins results in a failure of hTERT nuclear import, and the resulting cytoplasmic hTERT is degraded by ubiquitin-dependent proteolysis. Crystallographic analysis reveals that the bipartite NLS interacts with both the major and minor sites of importin-alpha proteins. We also show that Akt-mediated phosphorylation of S227 increases the binding affinity for importin-alpha proteins and promotes nuclear import of hTERT, thereby resulting in increased telomerase activity. These data provide details of a binding mechanism that enables hTERT to interact with the nuclear import receptors and of the control of the dynamic nuclear transport of hTERT through phosphorylation. Akt-mediated phosphorylation increases the binding affinity of hTERT for importin alpha to promote nuclear translocation.,Jeong SA, Kim K, Lee JH, Cha JS, Khadka P, Cho HS, Chung IK J Cell Sci. 2015 Jun 15;128(12):2287-301. doi: 10.1242/jcs.166132. Epub 2015 May , 21. PMID:25999477[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. Loading citation details.. Citations 8 reviews cite this structure No citations found See AlsoReferences
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Categories: Homo sapiens | Large Structures | Cho HS | Kim KL | Yoo JH
