MOLECULAR CHAPERONES AND IG BIOSYNTHESIS

描述（改编自研究者摘要）：正常发育和 免疫系统的功能部分取决于适当的组装， 免疫球蛋白（IG）受体和分泌蛋白的表达。像所有 分泌途径蛋白，IG分子被合成、折叠和组装 在内质网（ER），但不像大多数异聚体蛋白， 是亚基表达的发育不对称性。分子 ER的伴侣蛋白在控制ER的折叠中起关键作用。 并确保不完全或不正确组装的IG 蛋白质不会离开这个细胞器因此，阐明机制， ER中哪种IG成熟受到控制对于理解如何控制免疫球蛋白是重要的。 确保免疫系统的正常发育。过去，IG重 和轻链也提供了一个很好的模型系统， ER质量控制体系的组成部分，并了解其 功能在上一个资助期间，我们的研究表明，IG 运输是在结构域折叠的水平上控制的，这与其他运输方式不同， 未折叠的蛋白质，未组装的重链似乎不循环和关闭 急诊监护人为了了解细胞机制， 为此，在本申请中提出实验以1）确定 GRP94（一种功能未知的主要ER伴侣）在维持重 处于展开状态的链，其能够与轻链组装， 2)鉴定和表征调节BiP的ATP酶循环的ER蛋白， ER分子伴侣，以便理解为什么它保持稳定地与IG重结合 在不存在轻链合成的情况下，和3）分离 DnaJ伴侣辅因子，其作用是帮助和稳定 hsp70分子伴侣与未折叠的蛋白质结合，以了解BiP如何与重链蛋白结合， 链条被控制。从本文概述的实验中获得的数据 该提案将增加我们对ER质量控制机制的理解 这对IG的生物合成和成熟至关重要。

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.