A structure-based model for the electrostatic interaction of the N-terminus of protein tau with the fibril core of Alzheimer’s Disease filaments

Although portions of tau protein within the microtubule binding region have been shown to form the ordered core of tau filaments, the structural details of how other regions of tau participate in filament formation are so far unknown. In an attempt to understand how the N-terminus of tau may interact with fibril core, we crystallized and determined the structure of the N-terminal segment 5 RQEFEV 10 of tau. Several lines of evidence have shown the importance of this segment for fibril formation. The crystal structure reveals an out-of-register Class 5 steric zipper with a wet and a dry interface. To examine the possible interaction of 5 RQEFEV 10 with the tau fibril core, we modeled the binding of the wet interface of the 5 RQEFEV 10 structure with the 313 VDLSKVTSKC 322 region of the Alzheimer’s Disease tau filament structures. This model is consistent with, and helps to explain previous findings on the possible interaction of these two segments, distant in sequence. In addition, we discuss the possible conservation of this interaction across multiple polymorphs of tau.