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6月27日北大化学生物学讲座-Prof. Xu Wu
发布时间:2017-06-23关键字:

 【化学生物学报告会】“Protein Lipidation in Signal Transduction”

报告人:

Prof. Xu Wu

Associate Professor, Harvard Medical School

报告题目: “Protein Lipidation in Signal Transduction”
时间:6月27日(周二)下午3:00

地点:化学院A717

摘要:

Protein S-palmitoylation is a dynamic post-translational modification attaching the 16-carbon palmitate to the cysteine residues, and is generally involved in regulating protein trafficking and membrane localization. In addition to palmitoyl acyltransferase (PAT)-mediated palmitoylation, some proteins could undergo non-enzymatic autopalmitoylation when bound to palmitoyl-Coenzyme A (CoA) directly. However, autopalmitoylation is poorly characterized, and many autopalmitoylated proteins remain unknown. We have developed activity-based chemical probes to label and profile PATs and autopalmitoylated proteins in cells. Here we show that TEA domain transcription factors (TEAD1-4 in mammals, and Scalloped in Drosophila) are autopalmitoylated at evolutionarily conserved cysteine residues under physiological palmitoyl-CoA concentrations, suggesting that TEADs possess intrinsic and weak PAT-like activities. TEADs are critical transcription factors regulating stem cell fate, organ size, and tumorigenesis. TEADs bind to the transcription co-activator YAP/TAZ, and regulate the transcriptional output of Hippo pathway. Structural studies showed that palmitate is covalently linked to TEAD1, revealing a new ligand-binding site in TEADs. Furthermore, palmitoylation is required for TEADs’ transcriptional function, and TEAD-mediated muscle differentiation and cancer cell profliferation. Our results suggest that TEAD autopalmitoylation might serve as a molecular switch regulating Hippo pathway transcriptional complexes. To the best of our knowledge, this is the first demonstration that transcription factors could be autopalmitoylated, thus linking palmitoylation to transcriptional regulation. Furthermore, we have identified novel small molecule inhibitors of TEAD’s intrinsic enzyme-like activities. The compound binds directly to the palmitate binding site, and block TEAD transcriptional functions in cancer cells, suggesting a novel approach to target these “undraggable” proteins. In addition, we have revealed the cell polarity complex protein Scribble (SCRIB) also requires palmitoylation for its proper junctional localization. This process is mediated by palmitoyl acyltransferase ZDHHC7. Loss of ZDHHC7 led to mislocalization of SCRIB and loss of cell polarity. In summary, we have developed unique chemical biology tools to reveal novel functions of dynamic protein lipidation in signal transductions, and novel therapeutic opportunities for cancers.




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