MOLECULAR CHAPERONES AND IG BIOSYNTHESIS

分子伴侣和 IG 生物合成

• 批准号: 6128889
• 负责人: Linda M Hendershot
• 金额: $ 28.33万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6128889
• 关键词: antibody formation; dogs; endoplasmic reticulum; immunoglobulin G; laboratory mouse; laboratory rabbit; molecular assembly /self assembly; molecular chaperones; protein binding; protein biosynthesis; protein folding; stress proteins; tissue /cell culture

DESCRIPTION (adapted from investigator's abstract): The normal development and function of the immune system is dependent, in part, on the proper assembly and expression of immunoglobulin (Ig) receptor and secreted proteins. Like all secretory pathway proteins, Ig molecules are synthesized, folded and assembled in the endoplasmic reticulum (ER), but unlike most heteromeric proteins, there is a developmental asymmetry in the expression of the subunits. The molecular chaperones of the ER play a critical role in controlling the folding of the individual subunits and ensuring that incompletely or improperly assembled Ig proteins do not leave this organelle. Therefore, elucidating the mechanisms by which Ig maturation in the ER is controlled is important to understanding how the proper development of the immune system is ensured. In the past, Ig heavy and light chains have also provided an excellent model system for identifying components of the ER quality control system and for understanding their function. During the last funding period, our studies revealed that Ig transport is controlled at the level of domain folding and that unlike other unfolded proteins, unassembled heavy chains do not appear to cycle on and off ER chaperones. To understand the cellular machinery that is responsible for this, experiments are proposed in the present application to 1) determine the role of GRP94 (a major ER chaperone of unknown function) in maintaining heavy chains in an unfolded state that is competent for assembly with light chains, 2) identify and characterize ER proteins that regulate the ATPase cycle of BiP, an ER chaperone, in order to understand why it remains stably bound to Ig heavy chains in the absence of light chain synthesis, and 3) isolate ER homologues of the DnaJ chaperone cofactor, which acts to aid and stabilize the binding of hsp70 chaperones to unfolded proteins to understand how BiP's binding to heavy chains is controlled. The data obtained from the experiments outlined in this proposal will increase our understanding of the ER quality control machinery that is so crucial to proper Ig biosynthesis and maturation.

描述（根据调查员的摘要改编）：正常发展和 免疫系统的功能部分取决于适当的组件，并且 免疫球蛋白（IG）受体和分泌蛋白的表达。像所有人一样 分泌途径蛋白，IG分子合成，折叠和组装 在内质网（ER）中，但与大多数异源蛋白不同， 是亚基表达中的发育不对称性。分子 急诊室的伴侣在控制折叠方面起着关键作用 单个亚基并确保不完全或不正确的Ig 蛋白质不会离开该细胞器。因此，通过 急诊室中哪些IG成熟对于理解如何 确保免疫系统的适当发展。过去，IG很重 轻型连锁店还提供了一个出色的模型系统来识别 ER质量控制系统的组成部分，以了解其 功能。在最后的资金期间，我们的研究表明IG 运输受到域折叠级别的控制 展开的蛋白质，未组装的重链似乎没有循环和关闭 ER伴侣。了解负责的蜂窝机械 本应用程序中提出了这个实验，以确定 GRP94（功能未知的主要ER伴侣）的作用在保持沉重 链条处于一个不断发展的状态，该状态有能力用轻链组装， 2）识别和表征调节BIP ATPase周期的ER蛋白， ER伴侣，以了解为什么它仍然稳定与IG重束 在没有轻链合成的情况下链，3）分离 DNAJ伴侣辅助因子，可帮助和稳定结合 HSP70伴侣以展开蛋白质，以了解BIP如何与重物结合 链被控制。从此概述的实验中获得的数据 建议将增加我们对ER质量控制机械的理解 这对于适当的IG生物合成和成熟至关重要。