ROLES OF P24 PROTEINS IN GLYCOSYLATION AND EXTRACELLULAR SIGNALING PATHWAYS

P24 蛋白在糖基化和细胞外信号通路中的作用

• 批准号: 7959714
• 负责人: PATRICIA BERNINSONE
• 金额: $ 16.1万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7959714
• 关键词: Binding; Biochemical; Biomedical Research; Caenorhabditis elegans; Carbohydrates; Cell surface; Clinical; Complex; Computer Retrieval of Information on Scientific Projects Database; Congenital Disorders; Defect; Endoplasmic Reticulum; Event; Exhibits; Extracellular Protein; Funding; Genes; Genetic; Glycoproteins; Golgi Apparatus; Grant; Human; Institution; Label; Lectin; Link; Membrane Proteins; Mutate; Mutation; Nematoda; Neurons; Organism; Pathway interactions; Play; Polysaccharides; Protein Family; Protein Glycosylation; Proteins; Research; Research Personnel; Resources; Role; Signal Pathway; Source; Surface; Syndrome; United States National Institutes of Health; Wheat Germ Agglutinins; blastomere structure; cell growth; extracellular; glycosylation; member; molecular recognition; mutant; nervous system development; protein transport; trafficking

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Complex carbohydrates on cell surface and extracellular proteins play essential roles in molecular recognition events critical to cell growth and differentiation. In humans, the emerging congenital disorders of glycosylation (CDGs) include severe multisystemic syndromes linked to abnormal protein glycosylation; most of the identified CDGs reflect disruptions of glycan biosynthetic pathways. Recent studies have revealed that glycosylation abnormalities and CDG clinical presentations can also be caused by defects in intracellular protein trafficking. Genetically tractable simple organisms provide an opportunity to study the regulatory mechanisms of these conserved pathways. We have identified three genes in the nematode Caenorhabditis elegans which, when mutated, elicit binding of the lectin Wheat Germ Agglutinin on the cuticle surface, suggesting a role in the modulation of one or more glycosylation pathways. These mutations inactivate members of a conserved protein family (p24) implicated in cargo selectivity of endoplasmic reticulum to Golgi transport. Interestingly, these mutants exhibit specific neuronal abnormalities (our preliminary results), offering the opportunity to explore the role of p24 activity on the development of the nervous system. We use genetic and biochemical approaches in C. elegans to pursue the following aims: 1) examine the relationship between p24 activity and protein glycosylation status, by analysis of metabolically labeled glycoproteins from wild type and mutant embryonic cells and lectin purified fractions; 2) explore extracellular signaling pathways as downstream targets of p24 activity, using double mutant analysis; and 3) exploit abnormal lectin binding to the cuticle surface to identify additional genes involved in surface protein glycosylation and trafficking.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 细胞表面的复合碳水化合物和细胞外蛋白质在细胞生长和分化的关键分子识别事件中发挥重要作用。在人类中，新出现的先天性糖基化疾病（CDG）包括与异常蛋白质糖基化相关的严重多系统综合征;大多数已鉴定的CDG反映了聚糖生物合成途径的中断。最近的研究表明，糖基化异常和CDG临床表现也可能是由细胞内蛋白质运输缺陷引起的。遗传上易于处理的简单生物体提供了一个机会，研究这些保守的途径的调控机制。我们已经确定了三个基因的线虫秀丽隐杆线虫，突变时，引起的凝集素小麦胚芽凝集素的角质层表面上的结合，这表明在一个或多个糖基化途径的调制中的作用。这些突变是一个保守的蛋白质家族（p24）的成员，涉及内质网对高尔基体运输的货物选择性。有趣的是，这些突变体表现出特定的神经元异常（我们的初步结果），提供了探索p24活性对神经系统发育的作用的机会。 我们使用遗传和生物化学的方法在C。elegans进行以下目标：1）通过分析来自野生型和突变型胚胎细胞的代谢标记的糖蛋白和凝集素纯化级分，研究p24活性和蛋白质糖基化状态之间的关系; 2）使用双突变分析，探索作为p24活性下游靶点的细胞外信号传导途径;和3）利用与角质层表面结合的异常凝集素来鉴定参与表面蛋白糖基化和运输的其它基因。