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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The initial substrate-binding site of γ-secretase is located on presenilin near the active site
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The initial substrate-binding site of γ-secretase is located on presenilin near the active site

机译：γ-分泌酶的初始底物结合位点位于早老素上的活性位点附近

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摘要

γ-Secretase is a structurally enigmatic multiprotein complex that catalyzes intramembrane proteolysis of a variety of substrates, including the amyloid β-protein precursor of Alzheimer's disease and the Notch receptor essential to cell differentiation. The active site of this transmembrane aspartyl protease apparently lies at the interface between two subunits of presenilin-1 (PS1); however, evidence suggests the existence of an initial substrate-binding site that is distinct from the active site. Here, we report that photoaf-finity probes based on potent helical peptide inhibitors and designed to mimic the amyloid β-protein precursor substrate bind specifically to the PS subunit interface, at a site close to the active site. The location of the helical peptide-binding site suggests that substrate passes between the two PS1 subunits to access the active site. An aggressive Alzheimer-causing mutation in PS1 strongly reduced photolabeling by a transition-state analogue but not by helical peptides, providing biochemical evidence that the pathological effect of this PS mutation is due to alteration of the active-site topography.
机译：γ-分泌酶是一种结构神秘的多蛋白复合物，可催化多种底物的膜内蛋白水解，包括阿尔茨海默氏病的淀粉样β蛋白前体和细胞分化所必需的Notch受体。该跨膜天冬氨酰蛋白酶的活性位点显然位于早老素-1（PS1）的两个亚基之间的界面。然而，证据表明存在与活性位点不同的初始底物结合位点。在这里，我们报告说，基于有效的螺旋肽抑制剂并设计为模仿淀粉样β蛋白前体底物的photoaf-finity探针在接近活性位点的位置特异性结合PS亚基界面。螺旋肽结合位点的位置表明底物在两个PS1亚基之间通过以进入活性位点。 PS1中引起激进的阿尔茨海默氏症的突变大大降低了过渡态类似物而不是螺旋肽的光标记作用，从而提供了生化证据，证明该PS突变的病理学效应是由于活性部位形态的改变。

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