AlphaFold 2 predicts opening of the tau hairpin conformation by Mapt mutations and the extent of opening reflects their location

Abstract

AbstractBackgroundDozens of Mapt mutations can cause FTD, but the molecular mechanisms involved are poorly understood. We recently reported that Pro301 mutations increase the susceptibility of full‐length tau (FLT) to caspase‐3 cleavage at Asp421, which produces the highly noxious C‐terminal fragment tauC3. We speculated that the increased susceptibility could be caused by exposing the cleavage site through impact on critical hairpin interactions between Ser432 and P301. In another study, we used the AI‐based AlphaFold 2 (AF2) algorithm to predict and compare structural models of FLT and tauC3. This revealed dramatic differences in their conformations: tauC3 has an open conformation while FLT is closed by a hairpin. We postulated that other Mapt mutations may also open the conformation of tau in the same way.MethodWe performed AF2 predictions on FASTA sequences of several 4‐repeat FLT variants: R5H, P301S, P301L, and R406W. We also obtained the predicted intramolecular distances between Ser432 and the MTBR to assess the effect of the mutations on the conformation of tau quantitatively.ResultThere were notable differences in the magnitude of opening across the variants. Rank order for openness (Figure) was tauC3 > P301L > P301S > R406W > R5H ∼ non‐mutated FLT. P301L had a strong effect that approximated the opening in tauC3. P301S and R06W had moderate effects, while R5H has a minimal effect.ConclusionThe finding that P301L’s effect was greater than that of P301S may be explained by leucine’s greater hydrophobicity. The relatively strong effect of both Pro301 mutations reflect this residue being closest to Ser432. The R406W mutation’s intermediate but lesser effect is consistent with its relative proximity to Ser432, while the lack of effect for R5H suggests that the extreme N‐terminus is minimally involved. Collectively, our data shows the power of AF2 to predict effects of sequence alterations. The findings also have important implications for understanding tau biology and the development of therapeutics for tauopathies.