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首页> 外文期刊>Biochimica et biophysica acta: BBA: International journal of biochemistry, biophysics and molecular biololgy. Proteins and Proteomics >Binding studies of truncated variants of the Abeta peptide to the V-domain of the RAGE receptor reveal Abeta residues responsible for binding.
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Binding studies of truncated variants of the Abeta peptide to the V-domain of the RAGE receptor reveal Abeta residues responsible for binding.

机译：截断的Abeta肽变体与RAGE受体的V结构域的结合研究显示了负责结合的Abeta残基。

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摘要

Alzheimer's disease (AD) symptoms correlate with the concentration of soluble, although not necessarily monomeric forms of Abeta peptide in the brain parenchyma. The RAGE receptor has been implicated as the protein responsible for active transport of Abeta from blood circulation to the brain. In murine models of AD, inhibition of the Abeta:RAGE interaction decreases the levels of Abeta in the brain. Inhibition of the Abeta:RAGE interaction would be a promising alternative for the therapy of AD. Rational design of an Abeta:RAGE interaction blocker requires detailed knowledge of the structure of the complex. However, the binding domain of RAGE is natively unfolded in physiological conditions, which severely hampers the application of classic methods of protein structure analysis to the design of an antagonist. Here, alternative methods are used to characterize the structural properties of the RAGE-ligand binding domain and to monitor the binding of a series of truncated variants of Abeta. Using intrinsic RAGE tryptophan fluorescence and mass spectrometry of non-covalent protein-ligand complexes we have identified shorter versions of Abeta that bind to the RAGE V-domain. We have also shown in cell culture experiments that a selected shortened version of Abeta effectively inhibits full-length Abeta, RAGE-mediated, cell uptake. Thus, a truncated version of Abeta capable of blocking its receptor-mediated internalization was established, revealing the binding code and providing the lead compound in the process of drug design.
机译：阿尔茨海默氏病（AD）症状与脑实质中Abeta肽的可溶性形式相关，尽管不一定是单体形式。 RAGE受体被认为是负责Abeta从血液循环到大脑主动转运的蛋白质。在AD的鼠模型中，抑制Abeta：RAGE相互作用会降低大脑中Abeta的水平。抑制Abeta：RAGE相互作用将是AD治疗的有希望的替代方法。合理设计Abeta：RAGE交互阻止程序需要了解复杂结构的详细知识。但是，RAGE的结合域在生理条件下是天然展开的，这严重阻碍了经典蛋白质结构分析方法在拮抗剂设计中的应用。在这里，替代方法用于表征RAGE-配体结合域的结构特性，并监测一系列截短的Abeta变体的结合。使用内在的RAGE色氨酸荧光和非共价蛋白-配体复合物的质谱分析，我们确定了与RAGE V域结合的Abeta的较短版本。我们还在细胞培养实验中显示，Abeta的选定缩短版本可以有效抑制RAGE介导的全长Abeta细胞摄取。因此，建立了能够阻断其受体介导的内在化的截短形式的Abeta，揭示了其结合代码并在药物设计过程中提供了先导化合物。

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