Conformational Dynamics of Transmembrane Domain 3 of Presenilin 1 Is Associated with the Trimming Activity of γ-Secretase
Conformational Dynamics of Transmembrane Domain 3 of Presenilin 1 Is Associated with the Trimming Activity of γ-Secretase
复制标题
DOI：
10.1523/jneurosci.0838-19.2019
复制
发表时间：
2019-10-23
影响因子：
5.3
通讯作者：
Tomita, Taisuke
中科院分区：
文献类型：
--
作者：
Cai, Tetsuo;Morishima, Kanan;Tomita, Taisuke
γ -分泌酶是一种膜内切割蛋白酶，它产生有毒的淀粉样β肽（A β），这是阿尔茨海默病的病理原因。γ -分泌酶的催化亚基是早老素1 (PS1)，它是一种具有亲水催化孔的多位膜蛋白。A - β的C端长度是由γ -分泌酶对其进行的修饰决定的，尽管其精确的机制在很大程度上仍然未知。在这里，我们发现人类PS1的跨膜结构域（TMD） 3参与了膜内亲水孔的形成。值得注意的是，TMD3的水可及性被点突变和修饰γ -分泌酶活性的化合物大大改变。TMD3水分可及性的变化也与A β 42产量相关。此外，TMD3和TMD7之间的交联导致对γ分泌酶调节剂的敏感性丧失，从而减少a β 42的产生。因此，我们的研究结果表明，TMD3的构象动力学是调节γ分泌酶的a β修剪活性的先决条件。
gamma-Secretase is an intramembrane-cleaving protease that generates the toxic species of the amyloid-beta peptide (A beta) that is responsible for the pathology of Alzheimer disease. The catalytic subunit of gamma-secretase is presenilin 1 (PS1), which is a polytopic membrane protein with a hydrophilic catalytic pore. The length of the C terminus of A beta is proteolytically determined by its processive trimming by gamma-secretase, although the precise mechanism still remains largely unknown. Here, we identified that transmembrane domain (TMD) 3 of human PS1 is involved in the formation of the intramembranous hydrophilic pore. Notably, the water accessibility of TMD3 was greatly altered by point mutations and compounds, which modify gamma-secretase activity. The changes in the water accessibility of TMD3 was also correlated with A beta 42 production. Moreover, crosslinking between TMD3 and TMD7 resulted in a loss of sensitivity to a gamma-secretase modulator that reduces A beta 42 production. Therefore, our findings indicate that the conformational dynamics of TMD3 is a prerequisite for regulation of the A beta trimming activity of gamma-secretase.