Abstract
Post-translationally modified tau is the primary component of tau neurofibrillary tangles, a pathological hallmark of Alzheimer's disease and other tauopathies. Post-translational modifications (PTMs) within the tau microtubule (MT)-binding domain (MBD), which encompasses two hexapeptide motifs that act as critical nucleating regions for tau aggregation, can potentially modulate tau aggregation as well as interactions with MTs and membranes. Here, we characterize the effects of a recently discovered tau PTM, lysine succinylation, on tau–tubulin interactions and compare these to the effects of two previously reported MBD modifications, lysine acetylation and tyrosine phosphorylation. As generation of site-specific PTMs in proteins is challenging, we used short synthetic peptides to quantify the effects on tubulin binding of three site-specific PTMs located within the PHF6∗ (paired helical filament [PHF] residues 275–280) and PHF6 (residues 306–311) hexapeptide motifs: K280 acetylation, Y310 phosphorylation, and K311 succinylation. We compared these effects to those observed for MBD PTM-mimetic point mutations K280Q, Y310E, and K311E. Finally, we evaluated the effects of these PTM-mimetic mutations on MBD membrane binding and membrane-induced fibril and oligomer formation. We found that all three PTMs perturb tau MT binding, with Y310 phosphorylation exerting the strongest effect. PTM-mimetic mutations partially recapitulated the effects of the PTMs on MT binding and also disrupted tau membrane binding and membrane-induced oligomer and fibril formation. These results imply that these PTMs, including the novel and Alzheimer's disease–specific succinylation of tau K311, may influence both the physiological and pathological interactions of tau and thus represent targets for therapeutic intervention.
Highlights
Alzheimer’s disease (AD) progresses in several stages, with tau neurofibrillary tangles and amyloid plaques accumulating in concert with cognitive impairment [1,2,3]
Because we previously showed that vesicles that are high in negatively charged lipid content efficiently drive tau aggregation [53], we used small unilamellar vesicles (SUVs) composed of 4:1 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) to 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-Lserine (POPS). 15N–1H heteronuclear single quantum coherence (HSQC) NMR spectra of K18 in the presence of increasing concentrations of SUVs resulted in intensity losses in many signals, which we quantified as intensity ratios for signals in the presence versus absence of SUVs (Fig. 6)
We have characterized the effects of a novel diseaseassociated tau posttranslational modification (PTM), K311 succinylation, and shown that it locally perturbs the binding of the tau MT-binding domain (MBD) to tubulin, to an extent similar to that of K280 acetylation but to a lesser extent than Y310 phosphorylation
Summary
Alzheimer’s disease (AD) progresses in several stages, with tau neurofibrillary tangles and amyloid plaques accumulating in concert with cognitive impairment [1,2,3]. We investigate the ability of posttranslational modifications (PTMs) and their mimetics within two paired helical filament (PHF) nucleating regions, PHF6* and PHF6, to alter tau interactions and the ability of tau to aggregate and thereby to contribute to tau’s pathological role in forming toxic bodies. The phosphorylation of residue Y310 by the abelson tyrosine kinase (c-Abl) has been shown to influence tau-mediated MT assembly and tau aggregation [33] Both tyrosine phosphorylation and c-Abl are of interest because of potential pathogenic roles in AD and other tauopathies [31, 33,34,35,36,37,38], as well as other neurodegenerative diseases [39, 40]
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