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PDBsum entry 2pop
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Signaling protein/apoptosis
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PDB id
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2pop
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References listed in PDB file
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Key reference
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Title
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Xiap induces nf-Kappab activation via the bir1/tab1 interaction and bir1 dimerization.
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Authors
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M.Lu,
S.C.Lin,
Y.Huang,
Y.J.Kang,
R.Rich,
Y.C.Lo,
D.Myszka,
J.Han,
H.Wu.
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Ref.
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Mol Cell, 2007,
26,
689-702.
[DOI no: ]
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PubMed id
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Abstract
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In addition to caspase inhibition, X-linked inhibitor of apoptosis (XIAP)
induces NF-kappaB and MAP kinase activation during TGF-b and BMP receptor
signaling and upon overexpression. Here we show that the BIR1 domain of XIAP,
which has no previously ascribed function, directly interacts with TAB1 to
induce NF-kappaB activation. TAB1 is an upstream adaptor for the activation of
the kinase TAK1, which in turn couples to the NF-kappaB pathway. We report the
crystal structures of BIR1, TAB1, and the BIR1/TAB1 complex. The BIR1/TAB1
structure reveals a striking butterfly-shaped dimer and the detailed interaction
between BIR1 and TAB1. Structure-based mutagenesis and knockdown of TAB1 show
unambiguously that the BIR1/TAB1 interaction is crucial for XIAP-induced TAK1
and NF-kappaB activation. We show that although not interacting with BIR1, Smac,
the antagonist for caspase inhibition by XIAP, also inhibits the XIAP/TAB1
interaction. Disruption of BIR1 dimerization abolishes XIAP-mediated NF-kappaB
activation, implicating a proximity-induced mechanism for TAK1 activation.
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Figure 1.
Figure 1. Biochemical Analysis of the Interaction between the
BIR1 Domain of XIAP and the N-Terminal Domain of TAB1
(A)
Comigration of BIR1 and TAB1 N-terminal domain on gel filtration
chromatography.
(B) Duplicate responses (left) and
isotherms (right) for a 2-fold dilution series (0.143–18.25
μM) of TAB1 binding to surface-tethered BIR1 in an SPR
experiment.
(C) Duplicate responses (left) and isotherms
(right) for a 2-fold dilution series (0.143–18.25 μM) of TAB1
binding to surface-tethered BIR1-3 in an SPR experiment.
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Figure 5.
Figure 5. TAB1 Does Not Have Phosphatase Activity
(A)
Superposition of human TAB1 (yellow), human phosphatase PP2Cα
(green), and bacterial phosphatase PstP (pink).
(B)
Superposition of the active sites of TAB1 (yellow) and PP2Cα
(green). Two metal ions and one phosphate ion are bound at the
PP2Cα active site. Residues important for metal ion
coordination and catalysis are labeled in black for TAB1 and
green for PP2Cα.
(C) Only one Mn^2+ ion is bound at the
TAB1 active site when soaked with MnCl[2]. The F[o] − F[c] map
is shown at 10σ level.
(D) Electrostatic surface of the
PP2Cα active site. The location of the bound phosphate ion is
shown.
(E) Electrostatic surface of the same region in
TAB1.
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The above figures are
reprinted
by permission from Cell Press:
Mol Cell
(2007,
26,
689-702)
copyright 2007.
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