Folding of Alzheimer's core PHF subunit revealed by monoclonal antibody 423.

At present, the conformation-dependent monoclonal antibodies (mAb) provide the only information on folding of tau in the core PHF. Monoclonal antibody MN423 recognizes all and only those Alzheimer's disease (AD) core paired helical filaments (PHFs) subunits, which terminate at Glu391. Using recombinant analogs of the core PHF subunit corresponding to tau residues tau297-391, we found that the C-terminal pentapeptide (387)DHGAE(391) represented only one component of the structure recognized by mAb 423. Therefore, deletion mutants of the core subunit were generated to identify assembled parts of this conformational structure. We localized two spatially close components in the region 306-325 ((306)VQIVYK(311) and (321)KCGSL(325)) contributing to formation of the structure identified by mAb 423. Thus, the spatial proximity of three subunit segments (306)VQIVYK(311), (321)KCGSL(325) and (387)DHGAE(391) represents constraints for intramolecular folding of the core PHF subunit. Since PHF represents a compelling drug target in AD, structural knowledge presented could contribute to structure-based drug design.