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AbstractBackgroundTauC3 is an especially noxious C‐terminal tau fragment produced by caspase‐3 cleavage at Asp421. Two decades of accumulating evidence support its importance in the pathogenesis of AD and other tauopathies, notably FTD and PSP. TauC3 promotes aggregation and filament formation, recruits full length tau (FLT) to incipient fibrils, and despite low concentration in AD brain tissue relative to total tau, has been reported to account for substantially all the seeding activity in AD brain extracts. TauC3 has also been shown to slow fast axonal transport (FAT), with deleterious consequences. Although tau’s largely disordered structure prevents analysis by X‐ray crystallography, FRET analysis suggested the existence of a hairpin conformation in which the N‐terminus folds over the C‐terminus close to the MTBR. In this model, Ser432 is the point of closest contact with Pro301. Opening of the hairpin has been hypothesized to 1) make FLT prone to aggregation by exposing the MTBR, and 2) impair FAT by overexposing the phosphatase activating domain near the N‐terminus. We postulated that tauC3 cannot form the hairpin because it lacks Ser432 and thus has an “open” conformation. This would explain tauC3’s substantially increased pathogenicity compared to FLT. The AI‐based tool AlphaFold 2 (AF2) is being used to predict the conformation of many proteins with great accuracy. Applying it to FLT and tauC3 could provide valuable data about the hairpin and whether caspase cleavage alters it.MethodWe tested AF2’s ability to predict the conformation of 4‐repeat FLT and tauC3 from FASTA sequences, aligning the models produced with the MTBR.ResultAF2 modeling revealed a dramatically different conformation for tauC3 compared to FLT, specifically, an open conformation with the MTBR and N‐terminus far apart (Figure). Interestingly, it also revealed that the entire C‐terminus region of FLT starting at Gln423 is composed of a single α‐helix.ConclusionAF2 predictions support the existence of the hairpin conformation for tau and underscore the critical importance of residue 432 in maintaining it. The extended C‐terminus α‐helix may have functional implications. TauC3’s open conformation is consistent with its slowing of FAT and its ability to seed aggregation even at low concentrations.

01 Dec 2023·Alzheimer's & Dementia

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

Author: Chain, Daniel G ; Margolin, Richard A

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.

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