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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Activation and intrinsic γ-secretase activity of presenilin 1
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Activation and intrinsic γ-secretase activity of presenilin 1

机译：早老素1的活化和固有的γ-分泌酶活性

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摘要

A complex composed of presenilin (PS), nicastrin, PEN-2, and APH-1 is absolutely required for γ-secretase activity in vivo. Evidence has emerged to suggest a role for PS as the catalytic subunit of γ-secretase, but it has not been established that PS is catalytically active in the absence of associated subunits. We now report that bacterially synthesized, recombinant PS (rPS) reconstituted into liposomes exhibits γ-secretase activity. Moreover, an rPS mutant that lacks a catalytic aspartate residue neither exhibits reconstituted γ-secretase activity nor interacts with a transition-state γ-secretase inhibitor. Importantly, we demonstrate that rPS harboring mutations that cause early onset familial Alzheimer's disease (FAD) lead to elevations in the ratio of Aβ42 to Aβ40 peptides produced from a wild-type APP substrate and that rPS enhances the Aβ42/ Aβ40 peptide ratio from FAD-linked mutant APP substrates, findings that are entirely consistent with the results obtained in in vivo settings. Thus, γ-secretase cleavage specificity is an inherent property of the polypeptide. Finally, we demonstrate that PEN2 is sufficient to promote the endoproteolysis of PS1 to generate the active form of γ-secretase. Thus, we conclusively establish that activated PS is catalytically competent and the bimolecular interaction of PS1 and PEN2 can convert the PS1 zymogen to an active protease.
机译：由体内早老素（PS），尼卡斯汀，PEN-2和APH-1组成的复合物是体内γ-分泌酶活性的绝对必需。已有证据表明PS作为γ-分泌酶的催化亚基的作用，但尚未确定PS在没有相关亚基的情况下具有催化活性。我们现在报告说，重组为脂质体的细菌合成，重组PS（rPS）表现出γ-分泌酶活性。此外，缺乏催化天冬氨酸残基的rPS突变体既不表现出重构的γ-分泌酶活性，也不与过渡态γ-分泌酶抑制剂相互作用。重要的是，我们证明了带有导致早发性家族性阿尔茨海默氏病（FAD）的突变的rPS导致野生型APP底物产生的Aβ42与Aβ40肽的比率升高，并且rPS增强了FAD-A引起的Aβ42/Aβ40肽比率连锁突变APP底物，发现与体内设置获得的结果完全一致。因此，γ-分泌酶切割特异性是多肽的固有特性。最后，我们证明PEN2足以促进PS1的内蛋白水解以产生活性形式的γ-分泌酶。因此，我们最终确定活化的PS具有催化能力，并且PS1和PEN2的双分子相互作用可以将PS1酶原转化为活性蛋白酶。

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  • 作者

    Kwangwook Ahn; Christopher C. Shelton; Yuan Tian; Xulun Zhang; M. Lane Gilchrist; Sangram S. Sisodia; Yue-Ming Li;

  • 作者单位

    Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

    Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065,Department of Pharmacology;

    Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065,Department of Physiology, Biophysics and Systems Biology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021;

    Center for Molecular Neurobiology, University of Chicago, Chicago, IL 60637;

    Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065,Department of Chemical Engineering and Department of Biomedical Engineering, City College of the City University of New York, New York, NY 10031;

    Center for Molecular Neurobiology, University of Chicago, Chicago, IL 60637;

    Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065,Department of Pharmacology;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    intermembrane-cleaving proteases; notch; presenilinase; reconstitution;

    机译：跨膜切割蛋白酶;缺口;早老素酶;重构;

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