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首页> 外文期刊>Biochemistry >Pen-2 Is Essential for γ-Secretase Complex Stability and Trafficking but Partially Dispensable for Endoproteolysis
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Pen-2 Is Essential for γ-Secretase Complex Stability and Trafficking but Partially Dispensable for Endoproteolysis

机译：Pen-2对于γ-分泌酶复杂的稳定性和贩运必不可少，但对于内切骨溶解则是部分不需要的

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The 19-transmembrane γ-secretase complex generates the amyloid β-peptide of Alzheimer's disease by intramembrane proteolysis of the β-amyloid precursor protein. This complex is comprised of presenilin, Aph1, nicastrin, and Pen-2. The exact function and mechanism of the highly conserved Pen-2 subunit remain poorly understood. Using systematic mutagenesis, we confirm and extend our understanding of which key regions and specific residues play roles in various aspects of γ-secretase function, including maturation, localization, and activity, but not processivity. In general, mutations (1) within the first half of transmembrane domain (TMD) 1 of Pen-2 decreased PS1 endoproteolysis and γ-secretase proteolytic activity, (2) within the second half of TMD1 increased proteolytic activity, (3) within the cytosolic loop region decreased proteolytic activity, (4) within TMD2 decreased PS1 endoproteolysis, (5) within the first half of TMD2 decreased proteolytic activity, and (6) within C-terminal residues decreased proteolytic activity. Specific mutational effects included N33A in TMD1 causing an increase in γ-secretase complexes at the cell surface and a modest decrease in stability and the previously unreported I53A mutation in the loop region reducing stability 10-fold and proteolytic activity by half. In addition, we confirm that minor PS1 endoproteolysis can occur in the complete absence of Pen-2. Together, these data suggest that rather than solely being a catalyst for γ-secretase endoproteolysis, Pen-2 may also stabilize the complex prior to PS1 endoproteolysis, allowing time for full assembly and proper trafficking.
机译：19跨膜γ-分泌酶复合物通过β-淀粉样蛋白前体蛋白的膜内蛋白水解作用产生阿尔茨海默氏病的淀粉样蛋白β-肽。该复合物由早老素，Aph1，尼卡斯特林和Pen-2组成。高度保守的Pen-2亚基的确切功能和机制仍然知之甚少。通过系统诱变，我们确认并扩展了我们对哪些关键区域和特定残基在γ分泌酶功能的各个方面（包括成熟，定位和活性，而不是合成能力）中发挥作用的理解。一般而言，Pen-2的跨膜结构域（TMD）1上半部的突变降低PS1内蛋白水解和γ分泌酶的蛋白水解活性，（2）TMD1的后半段内的突变提高蛋白水解活性，（3）胞质环区域降低了蛋白水解活性，（4）在TMD2中降低了PS1内切蛋白水解作用，（5）在TMD2的前半部分内降低了蛋白水解活性，（6）在C末端残基内降低了蛋白水解活性。特定的突变作用包括TMD1中的N33A引起细胞表面γ-分泌酶复合物的增加和稳定性的适度降低，以及之前未报告的环区I53A突变使稳定性降低了10倍，蛋白水解活性降低了一半。此外，我们确认在Pen-2完全不存在的情况下会发生少量PS1内蛋白水解。总之，这些数据表明，Pen-2不仅可以单独用作γ-分泌酶内蛋白水解的催化剂，还可以在PS1内蛋白水解之前稳定复合物，从而为完整组装和正确运输留出时间。

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