DEGRADATION OF THE TRANSMEMBRANE DOMAIN OF APP

描述(摘自摘要) 该提案的总体目标是澄清一些 人力资本流动的基本路径和基本机制 I型膜跨膜结构域(TMD)的降解 内质网中的横跨蛋白质。因为伽马- 淀粉样前体蛋白TMD的分泌酶加工 对淀粉样蛋白Abeta多肽的产生至关重要 确定Abeta的羧基末端长度，申请者 特别感兴趣的是研究可能有助于 在病理上更相关的Abeta42的生产 阿尔茨海默病(AD)。为了实现这些目标，他们 提出探索战区导弹防御基本机制的三个具体目标 蛋白质分解和降解，检查它们与伽马的关系 分泌过程和定义有助于Abeta的途径 制作。在第一个具体目标中，他们将利用一种新的探测器 他们专门设计来研究体内的分裂事件 膜。申请者提出五个子目标，旨在增加 我们对经济全球化的基本机制和途径的理解 膜蛋白和TO的TMD降解和周转 研究这些途径对伽马分泌酶有何作用 正在处理。TMD退化有两种可能的方式， 伽马分泌酶过程可能存在关联：TMD降解可能会阻止 通过破坏错误折叠的APP底物生产淀粉样蛋白 否则会导致Abeta，也许更优先的是 病理性淀粉样蛋白1-42型。或者，降解剂 部分或不完全的途径可能导致Abeta的产生 退化。在第二个具体目标中，他们将分析潜在的 S2P在TMD周转和APP加工中的作用。这 蛋白水解酶最近被确定为裂解 跨膜区内的甾醇反应元件结合蛋白 初步数据显示，缺乏这种活性的细胞也 TMD探头周转不足。第三个具体目标是 为了描述APP处理和Abeta生产的路径， 一种独特的细胞株，主要分泌(占总Abeta的80%) 病理性Abeta1-42型淀粉样蛋白。身份识别和 优先产生的途径的特征 Abeta1-42可能有助于了解淀粉样蛋白的病理途径 阿尔茨海默氏症的产物。

DESCRIPTION (from abstract) The overall goals of the proposal are to elucidate some of the fundamental pathways and basic mechanisms for the turnover and degradation of the transmembrane domains (TMD) of type I membrane spanning proteins in the endoplasmic reticulum. Because the gamma- secretase processing of the TMD of the amyloid precursor protein (APP) is critical for the production of the amyloid Abeta peptide and determining the length of the carboxyl terminus of Abeta, the applicants are especially interested in examining pathways that may contribute to the production of the more pathologically relevant Abeta42 in Alzheimer's disease (AD). In order to accomplish these goals, they propose three specific aims that explore the basic mechanisms for TMD proteolysis and degradation, examine their relationship to gamma secretase processing and define the pathways that contribute to Abeta production. In the first specific aim, they will exploit a novel probe that they have designed to specifically examine cleavage events within the membrane. The applicants propose five sub-aims designed to increase our understanding of the basic mechanisms and pathways for the degradation and turnover of the TMD of membrane proteins and to investigate how these pathways may contribute to gamma secretase processing. There are two potential ways in which TMD degradation and gamma secretase processing may be linked: TMD degradation may prevent amyloid production by destroying mis-folded APP substrates that would otherwise give rise to Abeta and perhaps preferentially the more pathological Abeta1-42 form of amyloid. Alternatively, the degradative pathways may give rise to Abeta as a result of partial or incomplete degradation. In the second specific aim, they will analyze the potential role of site 2 protease (S2P) in TMD turnover and APP processing. This protease has recently been identified as the enzyme that cleaves the sterol response element binding protein within the transmembrane domain and preliminary data show that cells deficient in this activity are also deficient in the turnover of the TMD probe. The third specific aim is to characterize the pathways of APP processing and Abeta production in a unique cell line that secretes predominantly (80% of the total Abeta) the more pathological Abeta1-42 form of amyloid. The identification and characterization of the pathways that give rise preferentially to Abeta1-42 may provide insight into the pathological pathways of amyloid production in Alzheimer's disease.