Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10, Barcelona 08028, Spain.
CBMN (UMR 5248), University of Bordeaux-CNRS-IPB, Institut Européen de Chimie et Biologie, 2 rue Escarpit, Pessac 33600, France.
ACS Chem Neurosci. 2020 Oct 21;11(20):3358-3365. doi: 10.1021/acschemneuro.0c00470. Epub 2020 Oct 1.
Somatostatin (SST14) is strongly related to Alzheimer's disease (AD), as its levels decline during aging, it regulates the proteolytic degradation of the amyloid beta peptide (Aβ), and it binds to Aβ oligomers . Recently, the 3D structure of a membrane-associated β-sheet pore-forming tetramer (βPFO tetramer) has been reported. Here, we show that SST14 binds selectively to the βPFO tetramer with a value of ∼40 μM without binding to monomeric Aβ(1-42). Specific NMR chemical shift perturbations, observed during titration of SST14, define a binding site in the βPFO tetramer and are in agreement with a 2:1 stoichiometry determined by both native mass spectroscopy and isothermal titration calorimetry. These results enabled us to perform driven docking and model the binding mode for the interaction. The present study provides additional evidence on the relation between SST14 and the amyloid cascade and positions the βPFO tetramer as a relevant aggregation form of Aβ and as a potential target for AD.
生长抑素 14（SST14）与阿尔茨海默病（AD）密切相关，因为其水平在衰老过程中下降，它可以调节淀粉样β肽（Aβ）的蛋白水解降解，并且可以与 Aβ寡聚物结合。最近，报道了一种膜相关的β-折叠孔形成四聚体（βPFO 四聚体）的三维结构。在这里，我们表明 SST14 选择性地与 βPFO 四聚体结合，其值约为 40 μM，而不与单体 Aβ（1-42）结合。在 SST14 滴定过程中观察到的特异性 NMR 化学位移扰动，在 βPFO 四聚体中定义了一个结合位点，并且与通过天然质谱和等温滴定量热法确定的 2:1 化学计量数一致。这些结果使我们能够进行驱动对接并对相互作用的结合模式进行建模。本研究为 SST14 与淀粉样蛋白级联之间的关系提供了更多证据，并将βPFO 四聚体定位为 Aβ的相关聚集形式，以及 AD 的潜在靶标。
