The amyloid transition of the neuronal protein tau from intrinsically disordered state to ordered fibrils represents a hallmark of Alzheimer’s and related diseases, commonly called tauopathies. Tau stabilizes the axonal microtubule network, which is regulated by subtle post-translational modifications (PTMs) to generate physiological tau proteoforms that control its function. Aberrant PTMs, especially hyperphosphorylation by a variety of kinases, promote pathological accumulation of tau in neurofibrillary tangles. However, why phosphoprotein phosphatases (PPPs), the enzymes responsible for dephosphorylation, fail to counteract this pathology remains unknown. Using solution NMR spectroscopy combined with other biophysical techniques, we report the atomic-resolution view of two major tau-PPPs axes: PP2A, and PP2B (calcineurin). By leveraging our prior insights into the substrate recruitment mechanisms of PP2A holoenzymes, we show that direct tau recruitment at PP2A:B55 and PP2A:PR70 holoenzyme complexes occurs via distinct motifs on tau targeted by respective regulatory subunits (i.e., B55 and PR70). Similarly, calcineurin (CN) binding region of tau contains a putative non-canonical PxIxIT SLiM (short linear motif) engaged with CN-A subunit. Both PP2A and CN specific recruitment regions overlap with the PHF6 motifs of tau in the microtubule-binding repeats that are sequestered at the fibril interface, suggesting a potential correlation between the amyloid transition and impaired PPP “visibility” of tau. Moreover, we note specific dephosphorylation preferences toward certain tau phosphosites targeted by PP2A and CN, supporting the hypothesis that impairment of a specific PPP recruitment due to aberrant PTMs at their interaction regions may coincide with hyperphosphorylation. The central impact of the findings will yield new basic and clinical discoveries about how tau dephosphorylation is regulated in healthy brains, along with insights into shifts in the tau sensitivity of PPP interactome during pathogenic transition.
Katti et al. (Sun,) studied this question.