Dynamic interactions and Ca2+-binding modulate the holdase-type chaperone activity of S100B preventing tau aggregation and seeding

Abstract

The microtubule-associated protein tau is implicated in the formation of oligomers and fibrillar aggregates that evade proteostasis control and spread from cell-to-cell. Tau pathology is accompanied by sustained neuroinflammation and, while the release of alarmin mediators aggravates disease at late stages, early inflammatory responses encompass protective functions. This is the case of the Ca2+-binding S100B protein, an astrocytic alarmin which is augmented in AD and which has been recently implicated as a proteostasis regulator, acting over amyloid β aggregation. Here we report the activity of S100B as a suppressor of tau aggregation and seeding, operating at sub-stoichiometric conditions. We show that S100B interacts with tau in living cells even in microtubule-destabilizing conditions. Structural analysis revealed that tau undergoes dynamic interactions with S100B, in a Ca2+-dependent manner, notably with the aggregation prone repeat segments at the microtubule binding regions. This interaction involves contacts of tau with a cleft formed at the interface of the S100B dimer. Kinetic and mechanistic analysis revealed that S100B inhibits the aggregation of both full-length tau and of the microtubule binding domain, and that this proceeds through effects over primary and secondary nucleation, as confirmed by seeding assays and direct observation of S100B binding to tau oligomers and fibrils. In agreement with a role as an extracellular chaperone and its accumulation near tau positive inclusions, we show that S100B blocks proteopathic tau seeding. Together, our findings establish tau as a client of the S100B chaperone, providing evidence for neuro-protective functions of this inflammatory mediator across different tauopathies.

Inhibition of Tau seeding by targeting Tau nucleation core within neurons with a single domain antibody fragment

“… 61 The conversion from an inert Tau monomer to a seed-competent monomer would thus involve an increased accessibility of the PHF motifs. 61 Interestingly, several chaperones with Tau anti-aggregation activities, such as Hsc70, Hsp60, DnaJA2, and S100B 62 proteins, bind to regions overlapping PHF6, and in a weaker manner PHF6∗. Thus, one major mechanism of the anti-aggregation activities of these chaperones is likely the binding of Tau in the PHF region.…”

The effects of voluntary running exercise on the astrocytes of the medial prefrontal cortex in APP/PS1 mice

“…Evidence has shown that S100B is produced by astrocytes and plays roles both intracellularly and extracellularly (Hagmeyer et al., 2017). S100B secreted by astrocytes is nontoxic (Hagmeyer et al., 2017) and interacts with Aβ42 (Cristovao et al., 2018) and tau (Moreira et al., 2021), delaying their aggregation and preventing neurotoxicity during early AD. In this study, we found that running exercise increased S100B levels in the mPFC but not in mPFC astrocytes in WT mice.…”

Tau liquid–liquid phase separation is modulated by the Ca2+‐switched chaperone activity of the S100B protein

“…Blinding was not possible because of limited human resources in carrying out the experiments, collection of the samples, and analysis of the results. No studies with cells are reported, and sample size calculation for biochemical and biophysical measurements was not performed; we used sample sizes ( n ) between 3 and 5 which are commonly used in similar studies (Boyko et al, 2019; Moreira et al, 2021; Singh et al, 2020). No exclusion criteria were pre‐determined, and no samples were excluded.…”