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PDBsum entry 2ovr
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Transcription/cell cycle
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PDB id
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2ovr
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References listed in PDB file
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Key reference
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Title
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Structure of a fbw7-Skp1-Cyclin e complex: multisite-Phosphorylated substrate recognition by scf ubiquitin ligases.
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Authors
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B.Hao,
S.Oehlmann,
M.E.Sowa,
J.W.Harper,
N.P.Pavletich.
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Ref.
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Mol Cell, 2007,
26,
131-143.
[DOI no: ]
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PubMed id
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Abstract
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The ubiquitin-mediated proteolysis of cyclin E plays a central role in
cell-cycle progression, and cyclin E accumulation is a common event in cancer.
Cyclin E degradation is triggered by multisite phosphorylation, which induces
binding to the SCF(Fbw7) ubiquitin ligase complex. Structures of the Skp1-Fbw7
complex bound to cyclin E peptides identify a doubly phosphorylated
pThr380/pSer384 cyclin E motif as an optimal, high-affinity degron and a singly
phosphorylated pThr62 motif as a low-affinity one. Biochemical data indicate
that the closely related yeast SCF(Cdc4) complex recognizes the multisite
phosphorylated Sic1 substrate similarly and identify three doubly phosphorylated
Sic1 degrons, each capable of high-affinity interactions with two Cdc4 phosphate
binding sites. A model that explains the role of multiple cyclin E/Sic1 degrons
is provided by the findings that Fbw7 and Cdc4 dimerize, that Fbw7 dimerization
enhances the turnover of a weakly associated cyclin E in vivo, and that Cdc4
dimerization increases the rate and processivity of Sic1 ubiquitination in vitro.
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Figure 1.
Figure 1. Structure of the Skp1-Fbw7-CycE^degC Complex
(A) Overall architecture of the complex, with the secondary
structure elements of Skp1, F box, and linker domains labeled.
Dotted lines indicate disordered regions.
(B) CycE^degC
binds across the narrow face of the Fbw7 β-propeller structure.
The eight Fbw7 blades and the strands for one blade are labeled.
(C) Sequence alignment of the cyclin E peptides used in
crystallization with other SCF^Fbw7 substrates. Arrow indicates
the type II β turn, cylinder the left-handed polyproline II
helix, dotted lines disordered regions, and crosses the residues
of CycE^degC and CycE^degC that contact Fbw7. The substrate
residues that match the structure-based degron motif (  -X-
-
-
-pT/S-P-P-X-pS/T,
with representing
a hydrophobic residue and X any amino acid) are highlighted in
yellow.
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Figure 2.
Figure 2. Cyclin E-Fbw7 Contacts in the Skp1-Fbw7-CycE^degC
and Skp1-Fbw7-CycE^degN Complexes
(A) Close-up view of the
Fbw7-CycE^degC interface showing interacting amino acids of Fbw7
(pink) and CycE^degC (light blue). Hydrogen bonds are shown as
white dotted lines. The Fbw7 blade strands that provide cyclin E
contacts are labeled.
(B) Close-up view of the
Fbw7-CycE^degN interface.
(C) Molecular surface
representation of the WD40 domain colored according to
conservation among Fbw7 13 orthologs and the Cdc4 and Pop1
homologs (Figure S1).
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The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(2007,
26,
131-143)
copyright 2007.
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