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Evolutionary History of Alzheimer Disease-Causing Protein Family Presenilins with Pathological Implications
Journal of Molecular Evolution ( IF 2.1 ) Pub Date : 2020-10-01 , DOI: 10.1007/s00239-020-09966-w
Ammad Aslam Khan 1, 2 , Raja Hashim Ali 3, 4 , Bushra Mirza 5
Affiliation  

Presenilin proteins make the catalytic component of γ-secretase, a multiprotein transmembrane protease, and are type II transmembrane proteins. Amyloid protein, Notch, and beta catenin are among more than 90 substrates of Presenilins. Mutations in Presenilins lead to defects in proteolytic cleavage of its substrate resulting in some of the most devastating pathological conditions including Alzheimer disease (AD), developmental disorders, and cancer. In addition to catalytic roles, Presenilin protein is also shown to be involved in many non-catalytic roles, i.e., calcium homeostasis, regulation of autophagy, and protein trafficking, etc. These proteolytic proteins are highly conserved and are present in almost all the major eukaryotic groups. Studies, performed on a wide variety of organisms ranging from human to unicellular dictyostelium, have shown the important catalytic and non-catalytic roles of Presenilins. In this study, we infer the evolutionary patterns and history of Presenilins as well as of other γ-secretase proteins. We show that Presenilins are the most ancient of the γ-secretase proteins and that Presenilins may have their origin in the last common ancestor (LCA) of Eukaryotes. We also demonstrate that Presenilin proteins generally lack diversifying selection during the course of their evolution. Through evolutionary trace analysis, we show that Presenilin protein sites that undergo mutations in Familial Alzheimer disease, are highly conserved in metazoans. Finally, we discuss the evolutionary, physiological, and pathological implications of our findings and propose that the evolutionary profile of Presenilins supports the loss of function hypothesis of AD pathogenesis.



中文翻译:

具有病理学意义的阿尔茨海默病引起蛋白家族早老素的进化史

早老素蛋白是 γ-分泌酶(一种多蛋白跨膜蛋白酶)的催化成分,是 II 型跨膜蛋白。淀粉样蛋白、Notch 和 β 连环蛋白属于早老素的 90 多种底物。早老素的突变导致其底物的蛋白水解裂解缺陷,导致一些最具破坏性的病理状况,包括阿尔茨海默病 (AD)、发育障碍和癌症。除催化作用外,早老蛋白还被证明参与许多非催化作用,即钙稳态、自噬调节和蛋白质运输等。这些蛋白水解蛋白高度保守,几乎存在于所有主要的真核生物群。对各种生物进行的研究,从人类到单细胞盘基柄菌,已显示早老素的重要催化和非催化作用。在这项研究中,我们推断了早老素以及其他 γ-分泌酶蛋白的进化模式和历史。我们表明早老素是最古老的 γ-分泌酶蛋白,并且早老素可能起源于真核生物的最后一个共同祖先 (LCA)。我们还证明早老蛋白在其进化过程中通常缺乏多样化的选择。通过进化痕迹分析,我们表明在家族性阿尔茨海默病中发生突变的早老素蛋白位点在后生动物中高度保守。最后,我们讨论进化的、生理的、

更新日期:2020-10-02
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