Structures/mechanisms in a noncanonical ubiquitin-like protein transfer cascade

非典型泛素样蛋白转移级联的结构/机制

• 批准号: 8416428
• 负责人: BRENDA A SCHULMAN
• 金额: $ 31.62万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416428
• 关键词: Active Sites; Address; Aging; Autophagocytosis; Autophagosome; Binding; Biochemical; C-terminal; Cell division; Cells; Charge; Core Protein; Cysteine; Cytoplasmic Organelle; Cytoplasmic Protein; Defect; Degradation Pathway; Development; Diabetes Mellitus; Disease; Enzymatic Biochemistry; Enzymes; Eukaryotic Cell; Evaluation; Family; Government; Grant; Half-Life; Homeostasis; Homodimerization; Immunity; Infection; Knowledge; Lead; Ligation; Lipid Bilayers; Lipids; Lysosomes; Malignant Neoplasms; Mediating; Membrane; Metabolic Diseases; Modeling; Molecular; Neurodegenerative Disorders; Organelles; Pathway interactions; Persons; Phosphatidylethanolamine; Process; Proteins; Research; Role; Saint Jude Children' s Research Hospital; Series; Signal Transduction; Specificity; Structural Biochemistry; Structure; Surface; System; Therapeutic Agents; Ubiquitin; Ubiquitin Like Proteins; base; covalent bond; insight; intermolecular interaction; multidisciplinary; protein degradation; public health relevance; structural biology

DESCRIPTION (provided by applicant): Autophagy is an indispensable process mediating bulk protein degradation and organelle turnover in eukaryotic cells. During autophagy, cytoplasmic organelles and proteins are engulfed into a double-lipid bilayer "autophagosome" to be degraded in bulk upon autophagosome fusion with a lysosome. In addition to numerous proteins regulating autophagy, at least 15 distinct so-called "Atg" proteins are core components for autophagic membrane formation common to many forms of autophagy. Among these key core components are two families of ubiquitin-like proteins (Atg8 and Atg12), and their noncanonical conjugation systems [a noncanonical E1 enzyme (Atg7), two noncanonical E2 enzymes (Atg3 and Atg10), and a noncanonical E3 enzyme partially composed of a UBL (the Atg12~Atg5 conjugate, here ~ refers to a covalent bond)]. Despite the essential roles of these UBL conjugation cascades in the process of autophagy, and the association of defects in these pathways with numerous disease processes, our knowledge of the detailed enzymatic bases for UBL conjugation in autophagy remains relatively rudimentary. We propose to apply our expertise in UBL conjugation cascades to the mechanisms and specificities of noncanonical enzymes that conjugate UBLs during autophagy. Our research plan will utilize structural biology and biochemistry to understand mechanisms underlying Atg7-mediated initiation of autophagy UBL cascades (Aim 1) and ligation of autophagy UBLs to their targets (Aim 2).

描述（由申请人提供）：自噬是真核细胞中介导大量蛋白质降解和细胞器更新的不可或缺的过程。在自噬过程中，细胞质细胞器和蛋白质被吞噬到双脂双层“自噬体”中，以在自噬体与溶酶体融合时大量降解。除了许多调节自噬的蛋白质之外，至少15种不同的所谓的“Atg”蛋白质是许多形式的自噬共同的自噬膜形成的核心组分。这些关键核心成分包括两个泛蛋白样蛋白家族（Atg 8和Atg 12）及其非经典缀合系统[一种非经典E1酶（Atg 7）、两种非经典E2酶（Atg 3和Atg 10）以及一种部分由UBL组成的非经典E3酶（Atg 12 ~ Atg 5缀合物，这里~指的是共价键）]。尽管这些UBL共轭级联在自噬过程中的重要作用，以及这些途径中的缺陷与许多疾病过程的关联，但我们对自噬中UBL共轭的详细酶基础的了解仍然相对基本。我们建议将我们在UBL结合级联的专业知识应用于自噬过程中结合UBL的非经典酶的机制和特异性。我们的研究计划将利用结构生物学和生物化学来了解Atg 7介导的自噬UBL级联启动（Aim 1）和自噬UBL与其靶点连接（Aim 2）的机制。