Transmembrane Domain 9 of Presenilin Determines the Dynamic Conformation of the Catalytic Site of γ-Secretase*
Transmembrane Domain 9 of Presenilin Determines the Dynamic Conformation of the Catalytic Site of γ-Secretase*
复制标题
早老素跨膜结构域 9 决定 γ-分泌酶*催化位点的动态构象
DOI：
--
复制
发表时间：
2008
影响因子：
4.8
通讯作者：
B. de Strooper
中科院分区：
文献类型：
--
作者：
A. Tolia;Katrien Horré;B. de Strooper
用于治疗阿尔茨海默病的最突出的药物靶标之一是γ-分泌酶，其是一种负责产生淀粉样蛋白-β肽的多蛋白质复合物。复合物的催化核心在于早老素，一种多跨膜蛋白酶，其活性取决于位于跨膜结构域6和7中的两个天冬氨酸残基。我们最近通过半胱氨酸扫描诱变表明，这些rectatates面临着一个充满水的空腔中的脂质双层，展示了如何蛋白水解裂解的基板可以发生在膜内。在这里，我们表明，跨膜结构域9和疏水结构域VII在大细胞质环早老蛋白是动态结构部分，这个腔。疏水结构域VII与膜中的跨膜结构域7相关，可能促进水分子进入催化位点。另一方面，跨膜结构域9表现出高度灵活的结构，可能参与将底物转运到催化位点，以及与γ-分泌酶抑制剂的结合。保守的脯氨酸-丙氨酸-亮氨酸基序在该域的细胞质部分是非常接近的催化Asp 257，是至关重要的构象变化，导致激活的催化位点。我们还鉴定了该结构域中的独特突变体（I437 C），其特异性地阻断淀粉样蛋白-β肽的产生而不影响生理上不可或缺的Notch底物的加工。我们的数据最后结合起来，提出了一个模型的建筑组织和激活的催化位点的早老素。
One of the most prominent drug targets for the treatment of Alzheimer disease is γ-secretase, a multi-protein complex responsible for the generation of the amyloid-β peptide. The catalytic core of the complex lies on presenilin, a multi-spanning membrane protease, the activity of which depends on two aspartate residues located in transmembrane domains 6 and 7. We have recently shown by cysteine-scanning mutagenesis that these aspartates are facing a water-filled cavity in the lipid bilayer, demonstrating how proteolytic cleavage of the substrates can be taking place within the membrane. Here, we demonstrate that transmembrane domain 9 and hydrophobic domain VII in the large cytoplasmic loop of presenilin are dynamic structural parts of this cavity. Hydrophobic domain VII is associated with transmembrane domain 7 in the membrane, probably facilitating the entrance of water molecules in the catalytic site. Transmembrane domain 9, on the other hand, exhibits a highly flexible structure, potentially involved in the transport of substrates to the catalytic site, as well as in the binding of γ-secretase inhibitors. The conserved proline-alanine-leucine motif at the cytoplasmic part of this domain is extremely close to the catalytic Asp257 and is crucial for conformational changes leading to the activation of the catalytic site. We, also, identify a unique mutant in this domain (I437C) that specifically blocks amyloid-β peptide production without affecting the processing of the physiologically indispensable Notch substrate. Our data are finally combined to propose a model for the architectural organization and activation of the catalytic site of presenilin.
DOI：
10.1073/pnas.0511035103
发表时间：
2006-05
影响因子：
11.1
作者：
A. Wiita;Sri Rama Koti Ainavarapu;Hector H. Huang;Julio M. Fernandez
通讯作者：
A. Wiita;Sri Rama Koti Ainavarapu;Hector H. Huang;Julio M. Fernandez