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PDBsum entry 3wn7
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Transcription
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PDB id
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3wn7
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References listed in PDB file
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Key reference
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Title
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Kinetic, Thermodynamic, And structural characterizations of the association between nrf2-Dlgex degron and keap1.
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Authors
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T.Fukutomi,
K.Takagi,
T.Mizushima,
N.Ohuchi,
M.Yamamoto.
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Ref.
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Mol Cell Biol, 2014,
34,
832-846.
[DOI no: ]
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PubMed id
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Abstract
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Transcription factor Nrf2 (NF-E2-related factor 2) coordinately regulates
cytoprotective gene expression, but under unstressed conditions, Nrf2 is
degraded rapidly through Keap1 (Kelch-like ECH-associated protein 1)-mediated
ubiquitination. Nrf2 harbors two Keap1-binding motifs, DLG and ETGE.
Interactions between these two motifs and Keap1 constitute a key regulatory
nexus for cellular Nrf2 activity through the formation of a two-site binding
hinge-and-latch mechanism. In this study, we determined the minimum
Keap1-binding sequence of the DLG motif, the low-affinity latch site, and
defined a new DLGex motif that covers a sequence much longer than that
previously defined. We have successfully clarified the crystal structure of the
Keap1-DC-DLGex complex at 1.6 Å. DLGex possesses a complicated helix structure,
which interprets well the human-cancer-derived loss-of-function mutations in
DLGex. In thermodynamic analyses, Keap1-DLGex binding is characterized as
enthalpy and entropy driven, while Keap1-ETGE binding is characterized as purely
enthalpy driven. In kinetic analyses, Keap1-DLGex binding follows a
fast-association and fast-dissociation model, while Keap1-ETGE binding contains
a slow-reaction step that leads to a stable conformation. These results
demonstrate that the mode of DLGex binding to Keap1 is distinct from that of
ETGE structurally, thermodynamically, and kinetically and support our contention
that the DLGex motif serves as a converter transmitting environmental stress to
Nrf2 induction as the latch site.
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