Identification of F-Box Proteins in Toxoplasma

弓形虫中 F-Box 蛋白的鉴定

• 批准号: 9974899
• 负责人: Ira J Blader
• 金额: $ 24.78万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-07 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9974899
• 关键词: 26S proteasome; Address; Affect; Affinity; Animal Model; Animals; Biological Process; CRISPR screen; Cell Cycle; Cell physiology; Cells; Complex; Cullin Proteins; Cytoskeleton; Daughter; Enzymes; Eukaryota; F Box Domain; F-Box Proteins; Family; Genetic Transcription; Genome; Goals; Growth; Human; Hydroxylation; Lead; Lytic Phase; Mediating; Membrane; Modeling; Names; Paper; Parasites; Pathway interactions; Polyubiquitin; Protein Subunits; Proteins; Proteome; Proteomics; PubMed; RBX1 gene; Reporting; Role; Signal Transduction; Specificity; Toxoplasma; Toxoplasma gondii; Ubiquitin; Ubiquitination; Virulence; Work; arm; daughter cell; design; fitness; genome-wide; glycosylation; indexing; insight; novel; novel therapeutics; pathogen; plant fungi; protein degradation; protein function; receptor; recruit; scaffold; trafficking; ubiquitin-protein ligase

The SKP1/Cullin/F-box (SCF) class of E3 Ubiquitin Ligases is an evolutionarily conserved family of enzymes that regulate key cellular processes including the cell cycle, membrane trafficking, and signaling. The SCF-E3 is composed of four core components - Rbx1, Cullin1, SKP1, and a F-box protein. F-box proteins are the subunits that recruit substrate proteins to be poly-ubiquitinated by the SCF-E3, and they can also be directly poly-ubiquitinated. SCF-E3 dependent polyubiquitin serves as a signal for targeting to and degradation by the 26S-proteasome. Every eukaryote expresses a repertoire of F-box proteins, the majority of which have different affinities for different substrate proteins. Thus, F-box proteins are critical since they dictate which specific proteins will be ubiquitinated by the SCF-E3. In addition, F-box proteins can function independently of the SCF-E3. Thus, identifying and characterizing F-box proteins is central to understanding the functions of the SCF-E3 and remodeling of the proteome as cells engage new functions. This is important because protein degradation is as important as gene transcription in defining a cell's proteome. Here, we will identify essential SCF-E3 dependent F-box proteins, determine why they are essential, and identify the proteins that are their ubiquitination substrates. These studies will reveal how ubiquitin supports growth and virulence of a major human parasite. In addition, these findings will be relevant to related pathogens given the conservation of the SCF- E3 and many F-box proteins between Toxoplasma and other apicomplexan parasites.

SKP1/Cullin/F-box (SCF) 类 E3 泛素连接酶是一种进化型 调节关键细胞过程（包括细胞）的保守酶家族 循环、膜运输和信号传导。 SCF-E3由四个核心组成 成分 - Rbx1、Cullin1、SKP1 和 F-box 蛋白。 F-box 蛋白是 招募底物蛋白以被 SCF-E3 多泛素化的亚基，并且它们 也可以直接多聚泛素化。 SCF-E3 依赖性多聚泛素作为 用于靶向 26S-蛋白酶体并被 26S-蛋白酶体降解的信号。每个真核生物 表达一系列 F-box 蛋白，其中大多数具有不同的亲和力 对于不同的底物蛋白。因此，F-box 蛋白至关重要，因为它们决定了哪些 特定蛋白质将被 SCF-E3 泛素化。此外，F-box 蛋白还可以 功能独立于 SCF-E3。因此，识别和表征 F-box 蛋白质对于理解 SCF-E3 的功能和重塑 细胞发挥新功能时的蛋白质组。这很重要，因为蛋白质降解 在定义细胞蛋白质组时，它与基因转录一样重要。在这里，我们将识别 必需的 SCF-E3 依赖性 F-box 蛋白，确定它们为什么是必需的，以及 识别作为其泛素化底物的蛋白质。这些研究将揭示 泛素如何支持主要人类寄生虫的生长和毒力。此外， 鉴于 SCF 的保护，这些发现将与相关病原体相关 弓形虫和其他顶复门寄生虫之间的 E3 和许多 F-box 蛋白。