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| ==Structure of importin-alpha: dUTPase S11E NLS mutant complex== | | ==Structure of importin-alpha: dUTPase S11E NLS mutant complex== |
| <StructureSection load='4mz6' size='340' side='right' caption='[[4mz6]], [[Resolution|resolution]] 1.88Å' scene=''> | | <StructureSection load='4mz6' size='340' side='right'caption='[[4mz6]], [[Resolution|resolution]] 1.88Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[4mz6]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=4fds 4fds]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MZ6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4MZ6 FirstGlance]. <br> | | <table><tr><td colspan='2'>[[4mz6]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=4fds 4fds]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MZ6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MZ6 FirstGlance]. <br> |
| </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1elj|1elj]], [[3ukw|3ukw]], [[4mz5|4mz5]]</td></tr> | | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.88Å</td></tr> |
| <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Kpna2, Rch1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>
| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4mz6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mz6 OCA], [https://pdbe.org/4mz6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mz6 RCSB], [https://www.ebi.ac.uk/pdbsum/4mz6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mz6 ProSAT]</span></td></tr> |
| <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4mz6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mz6 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4mz6 RCSB], [http://www.ebi.ac.uk/pdbsum/4mz6 PDBsum]</span></td></tr> | |
| </table> | | </table> |
| == Function == | | == Function == |
| [[http://www.uniprot.org/uniprot/DUT_HUMAN DUT_HUMAN]] This enzyme is involved in nucleotide metabolism: it produces dUMP, the immediate precursor of thymidine nucleotides and it decreases the intracellular concentration of dUTP so that uracil cannot be incorporated into DNA.<ref>PMID:8805593</ref> [[http://www.uniprot.org/uniprot/IMA1_MOUSE IMA1_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. | | [https://www.uniprot.org/uniprot/DUT_HUMAN DUT_HUMAN] This enzyme is involved in nucleotide metabolism: it produces dUMP, the immediate precursor of thymidine nucleotides and it decreases the intracellular concentration of dUTP so that uracil cannot be incorporated into DNA.<ref>PMID:8805593</ref> |
| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| Phosphorylation adjacent to nuclear localization signals (NLSs) is involved in the regulation of nucleocytoplasmic transport. The nuclear isoform of human dUTPase, an enzyme that is essential for genomic integrity, has been shown to be phosphorylated on a serine residue (Ser11) in the vicinity of its nuclear localization signal; however, the effect of this phosphorylation is not yet known. To investigate this issue, an integrated set of structural, molecular and cell biological methods were employed. It is shown that NLS-adjacent phosphorylation of dUTPase occurs during the M phase of the cell cycle. Comparison of the cellular distribution of wild-type dUTPase with those of hyperphosphorylation- and hypophosphorylation-mimicking mutants suggests that phosphorylation at Ser11 leads to the exclusion of dUTPase from the nucleus. Isothermal titration microcalorimetry and additional independent biophysical techniques show that the interaction between dUTPase and importin-alpha, the karyopherin molecule responsible for `classical' NLS binding, is weakened significantly in the case of the S11E hyperphosphorylation-mimicking mutant. The structures of the importin-alpha-wild-type and the importin-alpha-hyperphosphorylation-mimicking dUTPase NLS complexes provide structural insights into the molecular details of this regulation. The data indicate that the post-translational modification of dUTPase during the cell cycle may modulate the nuclear availability of this enzyme.
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| Phosphorylation adjacent to the nuclear localization signal of human dUTPase abolishes nuclear import: structural and mechanistic insights.,Rona G, Marfori M, Borsos M, Scheer I, Takacs E, Toth J, Babos F, Magyar A, Erdei A, Bozoky Z, Buday L, Kobe B, Vertessy BG Acta Crystallogr D Biol Crystallogr. 2013 Dec;69(Pt 12):2495-505. doi:, 10.1107/S0907444913023354. Epub 2013 Nov 19. PMID:24311590<ref>PMID:24311590</ref>
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| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| ==See Also== | | ==See Also== |
| *[[Deoxyuridine 5'-triphosphate nucleotidohydrolase|Deoxyuridine 5'-triphosphate nucleotidohydrolase]] | | *[[DUTPase 3D structures|DUTPase 3D structures]] |
| *[[Importin|Importin]] | | *[[Importin 3D structures|Importin 3D structures]] |
| == References == | | == References == |
| <references/> | | <references/> |
| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Lk3 transgenic mice]] | | [[Category: Homo sapiens]] |
| [[Category: Kobe, B]] | | [[Category: Large Structures]] |
| [[Category: Marfori, M]] | | [[Category: Mus musculus]] |
| [[Category: Rona, G]] | | [[Category: Kobe B]] |
| [[Category: Vertessy, B G]]
| | [[Category: Marfori M]] |
| [[Category: Arm repeat]] | | [[Category: Rona G]] |
| [[Category: Importin]] | | [[Category: Vertessy BG]] |
| [[Category: Nucleus]] | |
| [[Category: Protein transport]]
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