Modulation of Amyloidogenic Protein Self-Assembly Using Tethered Small Molecules
Emma E. Cawood, Nicolas Guthertz, Jessica S. Ebo, Theodoros K. Karamanos, Sheena E. Radford, Andrew J. Wilson
Abstract
m), which assembles into amyloid fibrils associated with dialysis-related amyloidosis. Using this approach, we have trapped tetramers formed by ΔN6 under conditions which would normally lead to fibril formation and found that the degree of tetramer stabilization depends on the site of the covalent tether and the nature of the protein-fragment interaction. The covalent protein-ligand linkage enabled structural characterization of these trapped, off-pathway oligomers using X-ray crystallography and NMR, providing insight into why tetramer stabilization inhibits amyloid assembly. Our findings highlight the power of "post-translational chemical modification" as a tool to study biological molecular mechanisms.