A Phosphorylation‐Induced Turn Defines the Alzheimer’s Disease AT8 Antibody Epitope on the Tau Protein

Abstract

Post mortem biochemical staging of Alzheimers disease is currently based on immunochemical analysis of brain slices with the AT8a ntibody.T he epitope of AT8i s described around the pSer 202 /pThr 205 region of the hyperphosphorylated form of the neuronal protein tau. In this study, NMR spectroscopywas used to precisely map the AT8epitope on phosphorylated tau, and derive its defining structural features by ac ombination of NMR analyses and molecular dynamics.Aparticular turn conformation is stabilized by ah ydrogen bond of the phosphorylated Thr 205 residue to the amide proton of Gly 207 ,and is further stabilized by the two Arg residues opposing the pSer 202 /pThr 205 .

Epitope mapping and structural basis for the recognition of phosphorylated tau by the anti‐tau antibody AT8

“…Our structures do corroborate their finding of a direct interaction between AT8 and residues 205 and 207, but we extend the epitope to include all amino acids within 202–209. There are significant differences between the NMR/MD‐defined structure of the AT8 epitope peptide and the structure we determined in the crystal structure. Based on our crystal structures, a turn conformation of the AT8 epitope is not required for recognition by the AT8 antibody, and the AT8 epitope peptide is in a partially extended conformation with some polyproline type II helix character.…”

“…It is unknown whether this is the conformation of the AT8 epitope region when unphosphorylated in PHF‐tau or in solution. A recent study characterized the pS202/pT205 AT8 epitope peptide by NMR and molecular dynamics (MD) simulations. They report a helical turn in the structure of the peptide spanning P206–R209, induced by hydrogen‐bonding interactions between pT205 and the amide proton of G207.…”