A new electrochemical method that mimics phosphorylation of the core tau peptide K18 enables kinetic and structural analysis of intermediates and assembly

Voltage-calibrated, finely tunable protein assembly

“…The results reported here build on the prior demonstration that charge neutralization by low-voltage electroreduction can serve as a surrogate for signal-dependent phosphorylation to trigger protein folding and assembly [17,33]. What is new here is the demonstration that protein assembly, which can be proportionally driven by phosphorylation in vivo , can be size-proportionally driven by small increments of DC voltage in vitro .…”

“…The significance, wide generality and potential utility of this finding extends far beyond the squid's signal transducing reflectin, as signal-controlled phosphorylation is one of the most evolutionarily ancient and widely distributed mechanisms regulating protein structure and function throughout the kingdom of life. As one further example, we note that low-voltage electroreduction drives assembly of K18, the core peptide of tau—the brain protein that is pathologically driven by excess phosphorylation to assemble as amyloid in Alzheimer's and related neurodegenerative diseases [33]. The structural features shared by reflectin and K18 that enable their responses to be tuned by electroreduction include their thermodynamic drive to fold and assemble [16]; the restriction of that drive by the Coulombic repulsion of their cationic residues (primarily histidine in the case of reflectin, and lysine in the case of K18) initially maintaining both as intrinsically disordered proteins, and their physiological regulation by signal-activated phosphorylation, progressively neutralizing Coulombic repulsion to drive proportional folding and assembly.…”