Asynchronous Evolutionary Origins of Aβ and BACE1
Asynchronous Evolutionary Origins of Aβ and BACE1
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DOI：
10.1093/molbev/mst262
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发表时间：
2014-03-01
影响因子：
10.7
通讯作者：
Langeland, James A.
中科院分区：
文献类型：
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作者：
Moore, D. Blaine;Gillentine, Madelyn A.;Langeland, James A.
阿尔茨海默病（AD）特征性的神经退行性斑块由淀粉样蛋白β (A β)肽组成，该肽由淀粉样蛋白前体蛋白（APP）经β -分泌酶（β位点APP切割酶[BACE1]）和γ -分泌酶水解而成。尽管-分泌酶在后生动物中具有重要的功能，但BACE1或A β的重要作用尚未确定。因为它们唯一已知的功能导致疾病表型，我们试图从进化的角度来理解这些成分。我们发现在大多数动物类群中都发现了类似app的蛋白，但在颌口外没有发现与A β同源的序列，并且β切割位点仅在肉翼动物中保守。然而，BACE1酶可以通过基础脊索动物延伸到刺胞。然后，我们试图确定来自从未进化出a -的物种的BACE1是否可以蛋白水解含有a -的APP底物。我们证明来自基础脊索动物的BACE1是一个功能同源物，可以从全长人类APP中释放a β，这表明BACE1活性在a β之前至少进化了360个小时。
Neurodegenerative plaques characteristic of Alzheimer's disease (AD) are composed of amyloid beta (A beta) peptide, which is proteolyzed from amyloid precursor protein (APP) by beta-secretase (beta-site APP cleaving enzyme [BACE1]) and gamma-secretase. Although gamma-secretase has essential functions across metazoans, no essential roles have been identified for BACE1 or A beta. Because their only known function results in a disease phenotype, we sought to understand these components from an evolutionary perspective. We show that APP-like proteins are found throughout most animal taxa, but sequences homologous to A beta are not found outside gnathostomes and the beta cut site is only conserved within sarcopterygians. BACE1 enzymes, however, extend through basal chordates and as far as cnidaria. We then sought to determine whether BACE1 from a species that never evolved A beta could proteolyze APP substrates that include A beta. We demonstrate that BACE1 from a basal chordate is a functional ortholog that can liberate A beta from full-length human APP, indicating BACE1 activity evolved at least 360 My before A beta.