Conformational Models of APP Processing by Gamma Secretase Based on Analysis of Pathogenic Mutations.
Conformational Models of APP Processing by Gamma Secretase Based on Analysis of Pathogenic Mutations.
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DOI：
10.3390/ijms222413600
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发表时间：
2021-12-18
影响因子：
5.6
通讯作者：
Bezprozvanny I
中科院分区：
文献类型：
--
作者：
Kim M;Bezprozvanny I
淀粉样前体蛋白（APP）的蛋白水解过程在阿尔茨海默病（AD）的发病机制中起着关键作用。β和γ分泌酶对APP的连续切割导致Aβ40（非淀粉样蛋白生成）和Aβ42（淀粉样蛋白生成）肽的生成。早老素-1（PS1）或早老素-2（PS2）是γ-分泌酶的催化亚基。APP、PS1或PS2中的多个家族性AD（FAD）突变导致Aβ42：Aβ40比值增加以及患者脑中毒性Aβ42寡聚体和斑块的蓄积。在这项研究中，我们进行了APP与γ-分泌酶复合物的分子建模，并分析了APP和PS1中FAD突变的潜在影响。我们注意到APP跨膜结构域中的所有FAD突变都被预测会导致其二级结构的局部紊乱增加。基于对已知γ-分泌酶结构的结构分析，我们提出APP可以与γ-分泌酶形成两种潜在构象的复合物--M1和M2。在构象中，APP的M1跨膜结构域与PS1结构中跨膜结构域6（TM 6）之后的周膜结构域形成接触。在构象中，APP的M2跨膜结构域与PS1结构中的跨膜结构域7（TM 7）形成接触。通过分析PS1-FAD突变对局部蛋白质无序指数的影响，我们发现这些突变增加了M2的构象灵活性，降低了M1的构象灵活性。基于这些结果，我们提出，M2构象，而不是M1构象，γ分泌酶与APP复合物导致APP的淀粉样蛋白（Aβ42生成）加工。我们的模型预测，M1构象的APP加工有利于弯曲的膜，如早期内涵体的膜。相比之下，M2构象的APP加工可能受到相对平坦的膜的青睐，例如晚期内体和质膜的膜。这些预测与已发表的APP在不同亚细胞位置加工的生化分析一致。我们的研究结果还表明，特异性抑制剂Aβ42的生产可能会通过选择性靶向与APP的γ分泌酶复合物的M2构象。
Proteolytic processing of amyloid precursor protein (APP) plays a critical role in the pathogenesis of Alzheimer’s disease (AD). Sequential cleavage of APP by β and γ secretases leads to the generation of Aβ40 (non-amyloidogenic) and Aβ42 (amyloidogenic) peptides. Presenilin-1 (PS1) or presenilin-2 (PS2) play the role of a catalytic subunit of γ-secretase. Multiple familial AD (FAD) mutations in APP, PS1, or PS2 result in an increased Aβ42:Aβ40 ratio and the accumulation of toxic Aβ42 oligomers and plaques in patient brains. In this study, we perform molecular modeling of the APP complex with γ-secretase and analyze potential effects of FAD mutations in APP and PS1. We noticed that all FAD mutations in the APP transmembrane domain are predicted to cause an increase in the local disorder of its secondary structure. Based on structural analysis of known γ-secretase structures, we propose that APP can form a complex with γ-secretase in 2 potential conformations—M1 and M2. In conformation, the M1 transmembrane domain of APP forms a contact with the perimembrane domain that follows transmembrane domain 6 (TM6) in the PS1 structure. In conformation, the M2 transmembrane domain of APP forms a contact with transmembrane domain 7 (TM7) in the PS1 structure. By analyzing the effects of PS1-FAD mutations on the local protein disorder index, we discovered that these mutations increase the conformational flexibility of M2 and reduce the conformational flexibility of M1. Based on these results, we propose that M2 conformation, but not M1 conformation, of the γ secretase complex with APP leads to the amyloidogenic (Aβ42-generating) processing of APP. Our model predicts that APP processing in M1 conformation is favored by curved membranes, such as the membranes of early endosomes. In contrast, APP processing in M2 conformation is likely to be favored by relatively flat membranes, such as membranes of late endosomes and plasma membranes. These predictions are consistent with published biochemical analyses of APP processing at different subcellular locations. Our results also suggest that specific inhibitors of Aβ42 production could be potentially developed by selectively targeting the M2 conformation of the γ secretase complex with APP.
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DOI：
10.1124/jpet.112.199356
发表时间：
2013-03-01
影响因子：
3.5
作者：
Albright, Charles F.;Dockens, Randy C.;Tong, Gary
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影响因子：
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影响因子：
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作者：
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7.1
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