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Somatostatin, an In Vivo Binder to Aβ Oligomers, Binds to βPFOAβ(1-42) Tetramer.
ACS Chemical Neuroscience ( IF 5 ) Pub Date : 2020-09-11 , DOI: 10.1021/acschemneuro.0c00470 Eduard Puig 1, 2 , James Tolchard 2 , Antoni Riera 1, 3 , Natàlia Carulla 1, 2
ACS Chemical Neuroscience ( IF 5 ) Pub Date : 2020-09-11 , DOI: 10.1021/acschemneuro.0c00470 Eduard Puig 1, 2 , James Tolchard 2 , Antoni Riera 1, 3 , Natàlia Carulla 1, 2
Affiliation
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 in vivo. Recently, the 3D structure of a membrane-associated β-sheet pore-forming tetramer (βPFOAβ(1–42) tetramer) has been reported. Here, we show that SST14 binds selectively to the βPFOAβ(1–42) tetramer with a KD 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 βPFOAβ(1–42) 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 βPFOAβ(1–42) tetramer as a relevant aggregation form of Aβ and as a potential target for AD.
中文翻译:
生长抑素是Aβ寡聚体的体内结合剂,与βPFOAβ(1-42)四聚体结合。
生长抑素(SST14)与阿尔茨海默氏病(AD)密切相关,因为它的水平在衰老过程中下降,它调节淀粉样β肽(Aβ)的蛋白水解降解,并且在体内与Aβ寡聚体结合。最近,已经报道了与膜相关的β-片层成孔四聚体(βPFOAβ (1-42)四聚体)的3D结构。在这里,我们表明SST14选择性地与βPFOAβ (1-42)四聚体结合,其K D值为〜40μM ,而不与单体Aβ(1-42)结合。在SST14滴定过程中观察到的特定NMR化学位移扰动定义了βPFOAβ (1-42)中的结合位点四聚体和通过自然质谱和等温滴定量热法测定的2:1化学计量是一致的。这些结果使我们能够执行驱动式对接并为交互建模绑定模式。本研究为SST14与淀粉样蛋白级联反应之间的关系提供了更多证据,并将βPFOAβ (1-42)四聚体定位为Aβ的相关聚集形式,并可能成为AD的潜在靶标。
更新日期:2020-10-21
中文翻译:
生长抑素是Aβ寡聚体的体内结合剂,与βPFOAβ(1-42)四聚体结合。
生长抑素(SST14)与阿尔茨海默氏病(AD)密切相关,因为它的水平在衰老过程中下降,它调节淀粉样β肽(Aβ)的蛋白水解降解,并且在体内与Aβ寡聚体结合。最近,已经报道了与膜相关的β-片层成孔四聚体(βPFOAβ (1-42)四聚体)的3D结构。在这里,我们表明SST14选择性地与βPFOAβ (1-42)四聚体结合,其K D值为〜40μM ,而不与单体Aβ(1-42)结合。在SST14滴定过程中观察到的特定NMR化学位移扰动定义了βPFOAβ (1-42)中的结合位点四聚体和通过自然质谱和等温滴定量热法测定的2:1化学计量是一致的。这些结果使我们能够执行驱动式对接并为交互建模绑定模式。本研究为SST14与淀粉样蛋白级联反应之间的关系提供了更多证据,并将βPFOAβ (1-42)四聚体定位为Aβ的相关聚集形式,并可能成为AD的潜在靶标。