Chemical approach to study autopalmitoylation of transcription factors

研究转录因子自棕榈酰化的化学方法

• 批准号: 9188073
• 负责人: Xuelian Luo
• 金额: $ 37.83万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9188073
• 关键词: Acyltransferase; Affect; Binding; Biochemical; Carbon; Cells; Cerulenin; Chemicals; Colon; Complex; Crystallization; Cysteine; Disease; Drosophila genus; Enzymes; Event; Family; Fatty Acids; Fatty-acid synthase; Functional disorder; Genetic Transcription; Genetic study; Goals; Heart; Human; Hydrophobicity; In Vitro; Label; Light; Link; Lipids; Liver; Lung; Mammals; Membrane Proteins; Modification; Molecular; Muscle; Natural regeneration; Nuclear; Organ Size; Output; Ovary; Palmitates; Palmitoyl Coenzyme A; Pathway interactions; Pharmacology; Physiological; Play; Post-Translational Protein Processing; Process; Protein S; Proteins; Proteomics; Regulation; Role; Signal Transduction; Skin; Structure; Structure-Activity Relationship; Therapeutic Agents; Tissues; Transcription Coactivator; Tumor Suppression; Tumor Suppressor Proteins; X-Ray Crystallography; base; cofactor; fatty acid biosynthesis; fatty acid metabolism; human disease; improved; in vivo; inhibitor/antagonist; insight; mouse model; novel; novel strategies; palmitoylation; public health relevance; skeletal muscle differentiation; small molecule; small molecule inhibitor; tool; transcription factor; tumorigenesis

 DESCRIPTION (provided by applicant): Protein S-palmitoylation is a dynamic post-translational modification attaching the 16-carbon fatty acid (palmitate) to the cysteine residues. Genetic studies have shown that 23 of DHHC (Asp-His-His-Cys) domain-containing enzymes are protein palmitoyl acyltransferases (PATs). In addition, some proteins could undergo non-enzymatic autopalmitoylation when bound to palmitoyl-Coenzyme A (CoA) directly. To explore their functions, we have developed novel activity-based chemical probes to covalently label and profile PATs and autopalmitoylated proteins in cells. Through proteomic, biochemical and structural studies, we have discovered that the mammalian TEA domain family (TEAD/TEF) transcription factors (TEAD1-4) are autopalmitoylated proteins. TEADs are essential transcription factors that bind to the transcription co-activators YAP/TAZ and regulate Hippo pathway transcriptional output. Deregulation of TEAD-YAP complex has been linked to defective regeneration and organ size control in liver, skin, colon, and heart. Therefore, understanding this novel regulation will shed light on how fatty acid metabolism and autopalmitoylation regulate transcription factors. Our specific aims of this proposal include: (1) To determine the regulatory mechanism(s) of TEADs autopalmitoylation. (2) To investigate the roles of TEAD palmitoylation in regulating Hippo pathway in vitro and in vivo. (3) To develop small molecule inhibitors of TEAD autopalmitoylation as chemical tools.

 描述（由申请方提供）：蛋白S-棕榈酰化是一种动态翻译后修饰，将16碳脂肪酸（棕榈酸酯）连接至半胱氨酸残基。 遗传学研究表明，23种含有DHHC（Asp-His-His-Cys）结构域的酶是蛋白质棕榈酰酰基转移酶（PAT）。此外，当与棕榈酰辅酶A（CoA）直接结合时，一些蛋白质可以进行非酶促的自棕榈酰化。为了探索它们的功能，我们已经开发了新的基于活性的化学探针来共价标记和分析细胞中的PAT和自棕榈酰化蛋白。通过蛋白质组学、生物化学和结构研究，我们发现哺乳动物TEA结构域家族（TEAD/TEF）转录因子（TEAD 1 -4）是自棕榈酰化的蛋白质。TEAD是与转录共激活因子雅普/TAZ结合并调节Hippo途径转录输出的必需转录因子。TEAD-YAP复合物的失调与肝脏、皮肤、结肠和心脏中有缺陷的再生和器官大小控制有关。因此，了解这种新的调节将有助于阐明脂肪酸代谢和自棕榈酰化如何调节转录因子。我们的具体目标包括：（1）确定TEAD自棕榈酰化的调控机制。(2)探讨TEAD棕榈酰化在体内外Hippo通路中的作用。(3)开发TEAD自棕榈酰化的小分子抑制剂作为化学工具。