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.
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