Abstract
The Hippo pathway is a tumor suppressor pathway that is implicated in the regulation of organ size. The pathway has three components: the upstream regulatory factors, the kinase core, and the downstream transcriptional machinery, which consists of YAP, TAZ (transcription co-activators) and TEAD (transcription factor). Formation of YAP/TAZ-TEAD complexes leads to the transcription of growth-promoting genes. Herein, we report the crystal structure of TAZ-TEAD4 complex, which reveals two binding modes. The first is similar to the published YAP-TEAD structure. The second is a unique binding mode, whereby two molecules of TAZ bind to and bridge two molecules of TEAD4. We validated the latter using cross-linking and multi-angle light scattering. Using siRNA, we showed that TAZ knockdown leads to a decrease in TEAD4 dimerization. Lastly, results from luciferase assays, using YAP/TAZ transfected or knockdown cells, give support to the non-redundancy of YAP/TAZ co-activators in regulating gene expression in the Hippo pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acyltransferases
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Adaptor Proteins, Signal Transducing / chemistry*
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Binding Sites
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Cell Cycle Proteins
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DNA-Binding Proteins / chemistry*
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DNA-Binding Proteins / metabolism
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Mice
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Models, Molecular*
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Muscle Proteins / chemistry*
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Muscle Proteins / metabolism
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Phosphoproteins / chemistry*
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Phosphoproteins / metabolism
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Protein Binding
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Protein Conformation*
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Protein Interaction Domains and Motifs
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Protein Multimerization
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Recombinant Fusion Proteins
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Structure-Activity Relationship
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TEA Domain Transcription Factors
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Transcription Factors / chemistry*
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Transcription Factors / metabolism
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YAP-Signaling Proteins
Substances
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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DNA-Binding Proteins
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Muscle Proteins
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Phosphoproteins
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Recombinant Fusion Proteins
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TEA Domain Transcription Factors
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Tead4 protein, mouse
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Transcription Factors
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YAP-Signaling Proteins
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Yap1 protein, mouse
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Acyltransferases
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tafazzin protein, mouse