A phosphorylation-induced turn defines the Alzheimer's disease AT8 antibody epitope on the tau protein

Abstract

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Abstract Post mortem biochemical staging of Alzheimer's disease is currently based on immunochemical analysis of brain slices with the AT8 antibody. The epitope of AT8 is described around the pSer<inf>202</inf>/pThr<inf>205</inf> region of the hyperphosphorylated form of the neuronal protein tau. In this study, NMR spectroscopy was used to precisely map the AT8 epitope on phosphorylated tau, and derive its defining structural features by a combination of NMR analyses and molecular dynamics. A particular turn conformation is stabilized by a hydrogen bond of the phosphorylated Thr<inf>205</inf> residue to the amide proton of Gly<inf>207</inf>, and is further stabilized by the two Arg residues opposing the pSer<inf>202</inf>/pThr<inf>205</inf>. The AT8 epitope of the phosphorylated tau protein was mapped by NMR spectroscopy, and its defining structural features were derived by a combination of NMR analyses and molecular dynamics. A particular turn conformation is stabilized by a hydrogen bond of the phosphorylated Thr<inf>205</inf> residue (pThr<inf>205</inf>) to the amide proton of Gly<inf>207</inf>.