FOR 2290: Understanding Intramembrane Proteolysis

FOR 2290：了解膜内蛋白水解作用

• 批准号: 263531414
• 金额: --
• 依托单位: Zentrum für Biochemie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/263531414?language=en
• 关键词: 2290; Understanding; Intramembrane; Proteolysis

Intramembrane proteases cleave their substrates within or adjacent to membrane-spanning regions. Thereby, these unusual proteases affect a wide range of important biological functions and are implicated in several severe diseases including Alzheimer´s diseases (AD), the most common neurodegenerative disease. The great importance of research on intramembrane proteolysis is reflected by a recent special issue on Intramembrane Proteases in BBA Biomembranes (Vol. 1828, 2013) and a dedicated Gordon Research Conference on “Regulated Proteolysis of Cell Surface Proteins - Sheddases and Intramembrane-Cleaving Proteases: From Basic Research to Clinical Applications” (Ventura, March 30 to April 4, 2014). However, despite of more than a decade of research, we neither know the full repertoire of substrates and their functions nor do we understand the molecular properties that qualify a substrate as such. It is thus unclear what distinguishes substrates from non-substrates in structural terms. On the one hand, the transmembrane domains of known substrates exhibit a tremendous diversity of primary structures. On the other hand, only a fraction of single-span proteins are known as substrates and point mutations within them can strongly interfere with their proteolysis. This puzzling discrepancy between seemingly promiscuous and clearly sequence-specific processing of substrates indicates that their transmembrane domains share structural features that allow for specific recognition and cleavage by a given protease. The research group assembled in this proposal is uniquely qualified to solve the open question of how specificity of intramembrane proteolysis is achieved. Some of its members have a long and successful history in intramembrane proteolysis research and were among those who started the field while others have outstanding expertise in the structure/function analysis of transmembrane helices. Together, they will apply a cross-disciplinary approach to i) identify novel substrates for different types of intramembrane proteases and ii) explore for some paradigmatic cases how proteolysis is related to substrate/enzyme interaction and to the structure and conformational flexibility of the substrate transmembrane helices. This entails investigating the effect of disease-associated substrate mutations. Since intramembrane proteases are considered as relevant drug targets for various diseases a deep knowledge of their cleavage mechanism is crucially required in order to develop save and effective disease-modifying intramembrane protease inhibitors and/or modulators.

膜内蛋白酶在跨膜区域内或邻近跨膜区域切割其底物。因此，这些不寻常的蛋白酶影响广泛的重要生物学功能，并涉及几种严重的疾病，包括阿尔茨海默病（AD），最常见的神经退行性疾病。关于膜内蛋白水解研究的重要性反映在最近关于BBA生物膜中的膜内蛋白酶的特刊（Vol.1828，2013）和关于“细胞表面蛋白的调节蛋白水解- Sheddases和膜内裂解蛋白酶：从基础研究到临床应用”的专门Gordon研究会议（Ventura，March 30 to April 4，2014）。然而，尽管经过了十多年的研究，我们既不知道底物的全部组成及其功能，也不了解使底物本身合格的分子性质。因此，在结构方面，底物与非底物的区别尚不清楚。一方面，已知底物的跨膜结构域表现出一级结构的巨大多样性。另一方面，只有一小部分单跨度蛋白质被称为底物，并且其中的点突变可以强烈干扰它们的蛋白水解。这种看似混杂的和明确的序列特异性加工底物之间的令人困惑的差异表明，它们的跨膜结构域共享的结构特征，允许特定的识别和切割由给定的蛋白酶。在这项提案中组装的研究小组是唯一有资格解决如何实现膜内蛋白水解特异性的开放问题。它的一些成员在膜内蛋白水解研究方面有着悠久而成功的历史，并且是该领域的创始人之一，而其他成员则在跨膜螺旋的结构/功能分析方面具有杰出的专业知识。总之，他们将采用跨学科的方法，以i）确定不同类型的膜内蛋白酶的新底物和ii）探索一些典型的情况下，蛋白水解是如何与底物/酶的相互作用和底物跨膜螺旋的结构和构象的灵活性。这需要研究疾病相关底物突变的影响。由于膜内蛋白酶被认为是各种疾病的相关药物靶标，因此迫切需要对其切割机制的深入了解，以便开发安全有效的疾病修饰膜内蛋白酶抑制剂和/或调节剂。