Global Characterization of Protein Palmitoylation in Trypanosomes

锥虫中蛋白质棕榈酰化的整体表征

• 批准号: 8504116
• 负责人: David M. Engman
• 金额: $ 38.15万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8504116
• 关键词: 2-bromopalmitate; APPBP2 gene; Acylation; Acyltransferase; Affect; African; African Trypanosomiasis; Algorithms; Aminoacylation; Animal Model; Animals; Biological Models; Biology; Blood Circulation; Calcium-Binding Proteins; Cell physiology; Cells; Cellular Structures; Chagas Disease; Chemistry; Complex; Cutaneous Leishmaniasis; Data; Disease; Drug Targeting; Endoplasmic Reticulum; Enzymes; Eukaryota; Eukaryotic Cell; Genes; Genetic; Goals; Growth; In Vitro; Individual; Infection; Insecta; Knock-out; Leishmania; Light; Link; Lipids; Location; Maps; Mediating; Membrane; Membrane Microdomains; Modification; Mucocutaneous leishmaniasis; Myristates; N-Myristoylation; N-myristoyltransferase; N-terminal; Nature; Organism; Palmitates; Palmitic Acylation Site; Parasites; Peptides; Pharmaceutical Preparations; Post-Translational Protein Processing; Process; Protein Analysis; Proteins; Proteome; Qualifying; RNA Interference; Research; Risk; Signal Transduction; Signaling Molecule; Staging; Substrate Specificity; System; Time; Toxic effect; Transferase; Trypanosoma; Trypanosoma brucei brucei; Trypanosoma cruzi; Vaccines; Validation; Vesicle; Virulence; Virulence Factors; Visceral Leishmaniasis; Work; chemotherapy; homologous recombination; in vivo; interest; member; neglect; novel; palmitoylation; pathogen; prevent; public health relevance; tool

DESCRIPTION (provided by applicant): Global Characterization of Protein Palmitoylation in Trypanosomes Palmitoylation is a posttranslational modification of proteins that can affect how a protein interacts with lipids and proteins in a membrane compartment. Dual aminoacylation with myristate and palmitate is essential for targeting of proteins to lipid rafts, and is a common feature of key molecules in cell signaling. While N- myristoylation is carried out in the endoplasmic reticulum by a single N-myristoyltransferase, S-palmitoylation, and rarely N-palmitoylation (occurring on an N-terminal cys residue), is mediated by one of a number of palmitoyl acyltransferases (PATs), each having its own localization and substrate specificity. S-palmitoylation is essential for the functions of a number of important proteins and is essential in eukaryotes. Thus, the identification and linkage of specific PATs and their substrates constitutes a unique approach to systematic analysis eukaryote biology. In the African trypanosome, Trypanosoma brucei, our LC-MS/MS and RNAi data strongly suggest that protein palmitoylation is an abundant and important modification. In the proposed project, we will conduct a global analysis of protein palmitoylation in T. brucei in a five-year intensive research effort that will determine the palmitoylproteomes of T. brucei, identify the substrate profiles and functions of T. brucei PATs, and investigate this class of enzymes as potential targets for trypanocidal chemotherapy.

描述（由申请人提供）：锥虫中蛋白质棕榈酰化的整体表征棕榈酰化是蛋白质的翻译后修饰，可以影响蛋白质与膜区室中的脂质和蛋白质相互作用的方式。肉豆蔻酸酯和棕榈酸酯的双重氨酰化对于将蛋白质靶向脂筏至关重要，并且是常见的 细胞信号转导关键分子的特征。虽然 N-肉豆蔻酰化在内质网中由单一 N-肉豆蔻酰转移酶进行，但 S-棕榈酰化和很少的 N-棕榈酰化（发生在 N 末端 cys 残基上）是由多种棕榈酰酰基转移酶 (PAT) 之一介导的，每种都有其自己的定位和底物特异性。 S-棕榈酰化对于许多重要蛋白质的功能至关重要，并且对于 真核生物。因此，特定 PAT 及其底物的识别和连接构成了系统分析真核生物生物学的独特方法。在非洲锥虫布氏锥虫中，我们的 LC-MS/MS 和 RNAi 数据强烈表明蛋白质棕榈酰化是一种丰富且重要的修饰。在拟议的项目中，我们将在为期五年的深入研究工作中对布氏锥虫中的蛋白质棕榈酰化进行全球分析，以确定布氏锥虫的棕榈酰蛋白质组，确定布氏锥虫PAT的底物谱和功能，并研究此类酶作为杀锥虫化疗的潜在靶点。