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首页> 外文期刊>Biochemistry >The Amyloid Precursor Protein C-Terminal Fragment C100 Occurs in Monomeric and Dimeric Stable Conformations and Binds γ-Secretase Modulators
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The Amyloid Precursor Protein C-Terminal Fragment C100 Occurs in Monomeric and Dimeric Stable Conformations and Binds γ-Secretase Modulators

机译：淀粉样前体蛋白C末端片段C100发生在单体和二聚体的稳定构型中，并与γ分泌酶调节剂结合。

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The amyloid-β (Aβ) peptide is contained within the C-terminal fragment (β-CTF) of the amyloidnprecursor protein (APP) and is intimately linked to Alzheimer’s disease. In vivo,Aβ is generated by sequentialncleavage of β-CTF within the γ-secretase module. To investigate γ-secretase function, in vitro assays are innwidespread use which require a recombinant β-CTF substrate expressed in bacteria and purified fromninclusion bodies, termed C100. So far, little is known about the conformation of C100 under differentnconditions of purification and refolding. Since C100 dimerization influences the efficiency and specificity ofnγ-secretase cleavage, it is also of great interest to determine the secondary structure and the oligomeric state ofnthe synthetic substrate as well as the binding properties of small molecules named γ-secretase modulatorsn(GSMs) which we could previously show to modulate APP transmembrane sequence interactions [Richternet al. (2010) Proc.Natl. Acad. Sci.U.S.A. 107, 14597-14602].Here,we use circular dichroismand continuous-nwave electron spin resonance measurements to show that C100 purified in a buffer containing SDS atmicelle-nforming concentrations adopts a highly stable R-helical conformation, in which it shows little tendency tonaggregate or to form higher oligomers than dimers. By surface plasmon resonance analysis and molecularnmodeling we show that the GSM sulindac sulfide binds to C100 and has a preference for C100 dimers.
机译：淀粉样β蛋白（Aβ）包含在淀粉样前体蛋白（APP）的C末端片段（β-CTF）中，并且与阿尔茨海默氏病密切相关。在体内，通过在γ-分泌酶模块内依次切割β-CTF来生成Aβ。为了研究γ-分泌酶的功能，已广泛使用体外测定法，该方法需要在细菌中表达并从包涵体纯化的重组β-CTF底物，称为C100。到目前为止，对纯化和重折叠不同条件下C100的构象知之甚少。由于C100二聚化影响n-分泌酶裂解的效率和特异性，因此确定合成底物的二级结构和寡聚状态以及名为γ-分泌酶调节剂n（GSM）的小分子的结合特性也引起了人们的极大兴趣。可能以前显示调节APP跨膜序列相互作用[Richternet等。 （2010）美国国家自然科学杂志。学院美国科学[107，14597-14602]。在此，我们使用圆二色性和连续n波电子自旋共振测量结果显示，在含有SDS气溶胶形成浓度的缓冲液中纯化的C100具有高度稳定的R螺旋构象，几乎没有聚集的趋势。或形成比二聚体更高的低聚物。通过表面等离振子共振分析和分子建模，我们显示了GSM舒林酸硫化物与C100结合，并且优先选择C100二聚体。

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