TRANSIENT GLUCOSYLATION OF GLYCOPROTEINS

糖蛋白的瞬时糖基化

基本信息

批准号：
6386001
负责人：
ARMANDO JOSE PARODI
金额：
$ 7.5万
依托单位：
FUNDACION INSTITUTO LELOIR
依托单位国家：
美国
项目类别：
财政年份：
1990
资助国家：
美国
起止时间：
1990-08-15 至 2003-05-31
项目状态：
已结题

项目摘要

Protein glycosylation is initiated in the endoplasmic reticulum (ER) by transfer of an oligosaccharide (Glc3Man9GlcNAc2) to nascent polypeptide chains. Processing of the oligosaccharide by glucosidases I and II yields unglucosylated oligosaccharides that are reglucosylated by the UDP-Glc:glycoprotein glucosyltransferase (GT) only if the protein moieties of glycoproteins are not properly folded, as GT behaves as a sensor of glycoprotein conformations. Interaction of monoglucosylated glycoproteins (created by partialdeglucosylation of the transferred compound or by GT-mediated reglucosylation) with ER lectins (calnexin and calreticulin) facilitates acquisition of the proper tertiary structures and prevents secretion of not yet properly folded species. Folding facilitation mediated by the interaction of monoglucosylated glycoproteins and ER lectins is necessary for production of infective viral particles (vesicular stomatitis virus, HIV, hepatitis B virus) and also for the viability of yeasts when under severe ER stress conditions. The long term objective of the proposal is to gain thorough information of the structural features leading to the monoglucosylated glycoprotein-lectin interaction as this knowledge will undoubtedly provide useful information for understanding and/or preventing production of the etiological agents of several diseases. Within this long term objective, the Specific Aims of the proposed research are: a) to define the structural elements exclusively exposed in misfolded glycoproteins whose recognition is required for GT-mediated glucosylation; b) to define GT domains responsible for substrate donor (UDP-Glc), and substrate acceptor (N-oligosaccharide) recognition and for the exclusive glucosylation of misfolded species and c) to study the possibility that folding facilitation mediated by the interaction of cruzipain, a cysteine proteinase from the protozoan parasite Trypanosoma cruzi and ER lectins could be absolutely necessary for parasite infectivity. T. cruzi is the causative agent of a disease endemic in Latin America (Chagas's disease) that affects about 16 million people. Cruzipain has been identified as one of the T. cruzi virulence factors and has been found to be the only glycoprotein interacting with ER lectins in the protozoon.

蛋白质糖基化是通过将寡糖（GLC3MAN9GLCNAC2）转移到新生多肽链中的内质网（ER）中开始的。葡萄糖酶I和II对寡糖的加工会产生未通过UDP-GLC：糖蛋白葡萄糖基转移酶（GT）对葡萄糖糖基化的非葡萄糖基化的寡糖，仅当仅当糖蛋白部分的蛋白质部分就无法正常地折叠gt consect，而gtecoi则是gt concorn concorn concorn concorn concorn concorn concorn concorn condycors。单糖基化的糖蛋白（由转移化合物的部分二级葡萄糖基化或通过GT介导的再葡萄糖基化产生的相互作用）与ER凝集素（钙结合蛋白和钙蛋白酶）的相互作用，有助于对适当的三位型结构的获取，并促进适当的三物结构，并阻止尚未适当折叠的物种的分泌。折叠促进作用是由单戈糖基化糖蛋白和ER凝集素的相互作用介导的，对于在严重的ER应激条件下时，必不可少的感染性病毒颗粒（囊泡性气孔病毒，HIV，HIV，乙型肝炎病毒）以及酵母的生存能力是必要的。该提案的长期目标是获取导致一型糖基化糖蛋白 - 凝集素相互作用的结构特征的透彻信息，因为这些知识无疑将提供有用的信息，以理解和/或防止多种疾病的病因产生。在这个长期目标中，提议的研究的具体目的是：a）定义在错误折叠的糖蛋白中仅暴露的结构元素，这些糖蛋白的识别是GT介导的葡萄糖基所必需的； b) to define GT domains responsible for substrate donor (UDP-Glc), and substrate acceptor (N-oligosaccharide) recognition and for the exclusive glucosylation of misfolded species and c) to study the possibility that folding facilitation mediated by the interaction of cruzipain, a cysteine proteinase from the protozoan parasite Trypanosoma cruzi and ER lectins could be absolutely寄生虫感染所必需的。克鲁兹（T.克鲁齐帕已被确定为克鲁齐毒力因子之一，并被发现是原生动物中与er凝集素相互作用的唯一糖蛋白。