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PDBsum entry 5g05
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1569 a.a.
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84 a.a.
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524 a.a.
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55 a.a.
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56 a.a.
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460 a.a.
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25 a.a.
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488 a.a.
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723 a.a.
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504 a.a.
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182 a.a.
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59 a.a.
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604 a.a.
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688 a.a.
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492 a.a.
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15 a.a.
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26 a.a.
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484 a.a.
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References listed in PDB file
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Key reference
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Title
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Molecular mechanism of apc/c activation by mitotic phosphorylation.
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Authors
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S.Zhang,
L.Chang,
C.Alfieri,
Z.Zhang,
J.Yang,
S.Maslen,
M.Skehel,
D.Barford.
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Ref.
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Nature, 2016,
533,
260-264.
[DOI no: ]
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PubMed id
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Abstract
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In eukaryotes, the anaphase-promoting complex (APC/C, also known as the
cyclosome) regulates the ubiquitin-dependent proteolysis of specific cell-cycle
proteins to coordinate chromosome segregation in mitosis and entry into the G1
phase. The catalytic activity of the APC/C and its ability to specify the
destruction of particular proteins at different phases of the cell cycle are
controlled by its interaction with two structurally related coactivator
subunits, Cdc20 and Cdh1. Coactivators recognize substrate degrons, and enhance
the affinity of the APC/C for its cognate E2 (refs 4-6). During mitosis,
cyclin-dependent kinase (Cdk) and polo-like kinase (Plk) control Cdc20- and
Cdh1-mediated activation of the APC/C. Hyperphosphorylation of APC/C subunits,
notably Apc1 and Apc3, is required for Cdc20 to activate the APC/C, whereas
phosphorylation of Cdh1 prevents its association with the APC/C. Since both
coactivators associate with the APC/C through their common C-box and Ile-Arg
tail motifs, the mechanism underlying this differential regulation is unclear,
as is the role of specific APC/C phosphorylation sites. Here, using
cryo-electron microscopy and biochemical analysis, we define the molecular basis
of how phosphorylation of human APC/C allows for its control by Cdc20. An
auto-inhibitory segment of Apc1 acts as a molecular switch that in apo
unphosphorylated APC/C interacts with the C-box binding site and obstructs
engagement of Cdc20. Phosphorylation of the auto-inhibitory segment displaces it
from the C-box-binding site. Efficient phosphorylation of the auto-inhibitory
segment, and thus relief of auto-inhibition, requires the recruitment of
Cdk-cyclin in complex with a Cdk regulatory subunit (Cks) to a
hyperphosphorylated loop of Apc3. We also find that the small-molecule
inhibitor, tosyl-l-arginine methyl ester, preferentially suppresses APC/C(Cdc20)
rather than APC/C(Cdh1), and interacts with the binding sites of both the C-box
and Ile-Arg tail motifs. Our results reveal the mechanism for the regulation of
mitotic APC/C by phosphorylation and provide a rationale for the development of
selective inhibitors of this state.
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