Folding of N-rich erythrocyte remodeling proteins of malarial parasite

疟疾寄生虫富氮红细胞重塑蛋白的折叠

• 批准号: 7890450
• 负责人: Lauren Rebecca Pepper
• 金额: $ 4.76万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7890450
• 关键词: Adhesions; Adhesives; Affect; Amyloid; Amyloid Fibrils; Asparagine; Attention; Cells; Cessation of life; Characteristics; Clinical; Computer Simulation; Conserved Sequence; Cytoplasm; Disease; Disease Progression; Elements; Environment; Erythrocytes; Genome; Glutamine; Goals; Homologous Gene; Human; Huntington Disease; In Vitro; Individual; Infection; Lead; Libraries; Malaria; Mediating; Messenger RNA; Molecular Chaperones; Molecular Conformation; Nature; Organism; Parasites; Parkinson Disease; Phenotype; Plasmodium falciparum; Process; Protein Conformation; Protein Export Pathway; Protein Family; Proteins; Relative (related person); Role; Surface; Symptoms; System; Tertiary Protein Structure; Vaccines; Vacuole; Yeasts; alpha synuclein; amyloid structure; heat-shock proteins 40; human disease; in vivo; mortality; numb protein; prion-like; protein folding; protein function; public health relevance; response; trait

DESCRIPTION (provided by applicant): Protein domains rich in asparagine and glutamine often form amyloid structures. The malarial parasite Plasmodium falciparum has a genome significantly enriched in asparagine, and almost 25% of P. falciparum proteins have domains predicted to form amyloid conformations. The pathological state of the disease occurs when the parasite infects host erythrocytes. There are a number of asparagine-rich proteins exported out of the vacuole formed by the parasite into the surrounding red blood cell, yet the role of these proteins is not well understood. Additionally, there are a high number of heat shock protein 40 kDa (Hsp40) homologs secreted into the infected erythrocyte, presumably to help fold these low complexity proteins. The goal of this proposal is to understand the contribution of asparagine-rich proteins and Hsp40 homologs in the remodeling of infected erythrocytes. This will be accomplished by (1) characterizing the folding and amyloidogenic nature of exported P. falciparum proteins, (2) establishing the influence of Hsp40 homologs in the folding of characteristic asparagine-rich P. falciparum proteins, and (3) examining the amyloidogenicity of asparagine-rich proteins in vitro and in vivo. Because yeast expressing aggregation-prone proteins display distinct phenotypes, S. cerevisae will be used as an expression platform for much of this proposal. Yeast also provide an excellent system to investigate chaperone activity, and therefore will be used to assess the contribution of Hsp40 homologs to protein folding in infected erythrocytes. Additionally, the ability of asparagine-rich parasite proteins to form fibrils in vitro will be investigated. Infected erythrocytes will also be analyzed to look for the presence of amyloid fibrils. PUBLIC HEALTH RELEVANCE: Infection by P. falciparum, the most deadly malaria parasite, results in approximately two million deaths a year. In order to develop successful vaccines against this parasite, it is important to fully understand the remodeling of infected erythrocytes and the proteins involved in this process, which leads to the clinical symptoms and mortality of the disease.

描述（由申请人提供）：富含天冬酰胺和谷氨酰胺的蛋白质结构域通常形成淀粉样结构。恶性疟原虫的疟原虫具有明显富集在天冬酰胺中的基因组，而几乎25％的恶性疟原虫蛋白具有预测形成淀粉样蛋白构象的结构域。当寄生虫感染宿主红细胞时，疾病的病理状态发生。从寄生虫形成的液泡中导出了许多富含天冬酰胺的蛋白质，但这些蛋白质的作用尚不清楚。此外，有大量的热休克蛋白40 kDa（Hsp40）分泌到感染的红细胞中，大概是为了帮助折叠这些低复杂性蛋白。该建议的目的是了解富含天冬酰胺的蛋白质和HSP40同源物在被感染的红细胞重塑中的贡献。这将是通过（1）表征出口恶性疟原虫蛋白的折叠和淀粉样蛋白生成性质，（2）建立Hsp40同源物在特征富含天冬酰胺的恶性疟原虫蛋白的折叠中的影响，以及（3）（3）检查含芦丝蛋白质蛋白质蛋白质蛋白质的淀粉样蛋白的影响。由于表达聚集蛋白的酵母显示出不同的表型，因此酿酒酵母将用作大部分建议的表达平台。酵母还提供了一个很好的系统来研究伴侣活性，因此将用于评估HSP40同源物对感染红细胞中蛋白质折叠的贡献。此外，将研究富含天冬酰胺的寄生虫蛋白在体外形成原纤维的能力。还将分析感染的红细胞以寻找淀粉样蛋白纤维的存在。公共卫生相关性：最致命的疟疾寄生虫P. falciparum感染，每年大约有200万人死亡。为了针对这种寄生虫开发成功的疫苗，重要的是要充分了解感染红细胞的重塑以及参与此过程的蛋白质，从而导致疾病的临床症状和死亡率。