FOR 2290: Understanding Intramembrane Proteolysis

膜内蛋白水解酶在跨膜区域内或邻近区域裂解底物。因此，这些不寻常的蛋白水解酶影响广泛的重要生物学功能，并与几种严重疾病有关，包括阿尔茨海默病、S病(AD)，这是最常见的神经退行性疾病。最近一期关于BBA生物膜中的膜内蛋白水解酶的特刊(Vol.1828,2013)和专门的Gordon研究会议(Ventura，2014年3月30日至4月4日)反映了膜内蛋白分解研究的高度重要性。然而，尽管经过了十多年的研究，我们既不知道底物的全部谱系及其功能，也不了解构成底物的分子特性。因此，就结构而言，还不清楚底物和非底物的区别是什么。一方面，已知底物的跨膜结构域显示出巨大的一级结构多样性。另一方面，只有一小部分单跨距蛋白质被称为底物，它们内部的点突变可以强烈干扰它们的蛋白质分解。底物的表面混杂处理和明显的序列特异性处理之间的这种令人费解的差异表明，它们的跨膜域具有共同的结构特征，允许特定的蛋白酶特异性识别和切割。在这项提案中集合的研究小组是唯一有资格解决如何实现膜内蛋白分解的特异性这一开放问题的。它的一些成员在膜内蛋白分解研究方面有着悠久而成功的历史，是该领域的开创者之一，而另一些成员在跨膜螺旋的结构/功能分析方面拥有杰出的专业知识。他们将共同应用一种跨学科的方法来：i)为不同类型的膜内蛋白酶寻找新的底物；ii)在一些典型的情况下，探索蛋白质分解如何与底物/酶的相互作用以及底物跨膜螺旋的结构和构象灵活性有关。这需要研究与疾病相关的底物突变的影响。由于膜内蛋白水解酶被认为是各种疾病的相关药物靶点，为了开发安全有效的膜内蛋白水解酶抑制剂和/或调节剂，对其切割机制的深入了解是至关重要的。

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.