Understanding the molecular basis for the inhibition of the Alzheimer's Aβ-peptide oligomerization by human serum albumin using saturation transfer difference and off-resonance relaxation NMR spectroscopy
Understanding the molecular basis for the inhibition of the Alzheimer's Aβ-peptide oligomerization by human serum albumin using saturation transfer difference and off-resonance relaxation NMR spectroscopy
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DOI：
10.1021/ja067367
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发表时间：
2007-04-11
影响因子：
15
通讯作者：
Melacini, Giuseppe
中科院分区：
文献类型：
--
作者：
Milojevic, Julijana;Esposito, Veronica;Melacini, Giuseppe
人血清白蛋白（HSA）抑制人血浆中淀粉样β肽（A β）原纤维的形成。然而，目前还不知道HSA如何影响在A β纤维化的初始阶段发生的高毒性可溶性可扩散寡聚体的形成。因此，我们已经研究了溶液NMR的HSA与A β（12-28）肽，这已被证明是一个可靠的和稳定的模型，早期prefibrillar寡聚体，以及包含关键的决定因素的识别白蛋白的相互作用。为此，我们提出了一种新的NMR方法的基础上，通过饱和转移差和最近开发的非选择性非共振弛豫实验监测的A β在其抑制和过滤状态的比较分析。这种组合的NMR策略揭示了HSA的寡聚化抑制功能的机制，根据该机制，HSA优先靶向A β（12-28）的可溶性寡聚体而不是其单体状态。具体地，HSA覆盖位于A β寡聚体的生长和/或瞬时暴露位点处的暴露的疏水斑块，从而阻断另外的单体的添加和前原纤维组装体的生长。该模型不仅对阿尔茨海默病的药物治疗有意义，而且对淀粉样蛋白相关疾病的寡聚化抑制也有意义。此外，建议的NMR方法预计将是有用的其他寡聚化抑制剂以及其他淀粉样系统的作用机制的调查。
Human serum albumin (HSA) inhibits the formation of amyloid beta-peptide (A beta) fibrils in human plasma. However, currently it is not known how HSA affects the formation of the highly toxic soluble diffusible oligomers that occur in the initial stages of A beta fibrillization. We have therefore investigated by solution NMR the interaction of HSA with the A beta(12-28) peptide, which has been previously shown to provide a reliable and stable model for the early prefibrillar oligomers as well as to contain key determinants for the recognition by albumin. For this purpose we propose a novel NMR approach based on the comparative analysis of A beta in its inhibited and filtrated states monitored through both saturation transfer difference and recently developed nonselective off-resonance relaxation experiments. This combined NMR strategy reveals a mechanism for the oligomerization inhibitory function of HSA, according to which HSA targets preferentially the soluble oligomers of A beta(12-28) rather than its monomeric state. Specifically, HSA caps the exposed hydrophobic patches located at the growing and/or transiently exposed sites of the A beta oligomers, thereby blocking the addition of further monomers and the growth of the prefibrillar assemblies. The proposed model has implications not only for the pharmacological treatment of Alzheimer's disease specifically but also for the inhibition of oligomerization in amyloid-related diseases in general. In addition, the proposed NMR approach is expected to be useful for the investigation of the mechanism of action of other oligomerization inhibitors as well as of other amyloidogenic systems.