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PDBsum entry 4mz6
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Protein transport
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PDB id
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4mz6
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References listed in PDB file
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Key reference
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Title
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Phosphorylation adjacent to the nuclear localization signal of human dutpase abolishes nuclear import: structural and mechanistic insights.
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Authors
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G.Róna,
M.Marfori,
M.Borsos,
I.Scheer,
E.Takács,
J.Tóth,
F.Babos,
A.Magyar,
A.Erdei,
Z.Bozóky,
L.Buday,
B.Kobe,
B.G.Vértessy.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 2013,
69,
2495-2505.
[DOI no: ]
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PubMed id
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Abstract
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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-α, 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-α-wild-type and the
importin-α-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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