Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry*
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Amino Acid Sequence
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Animals
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Apoptosis Regulatory Proteins
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Cell Line
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Cells, Cultured
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Crystallography, X-Ray
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Dimerization
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Humans
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In Vitro Techniques
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Intracellular Signaling Peptides and Proteins / chemistry
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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Mice
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Mitochondrial Proteins / metabolism
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Models, Molecular
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Molecular Sequence Data
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Multiprotein Complexes
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NF-kappa B / metabolism*
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Phosphorylation
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Protein Structure, Tertiary
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Sequence Homology, Amino Acid
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Static Electricity
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Surface Plasmon Resonance
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X-Linked Inhibitor of Apoptosis Protein / chemistry*
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X-Linked Inhibitor of Apoptosis Protein / genetics
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X-Linked Inhibitor of Apoptosis Protein / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Apoptosis Regulatory Proteins
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DIABLO protein, human
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Intracellular Signaling Peptides and Proteins
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Mitochondrial Proteins
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Multiprotein Complexes
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NF-kappa B
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Recombinant Fusion Proteins
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TAB1 protein, MAPKKK activator, vertebrate
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TAB1 protein, human
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X-Linked Inhibitor of Apoptosis Protein
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XIAP protein, human