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

Guilherme G. Moreira, François-Xavier Cantrelle, Andrea Quezada, Filipa S. Carvalho, Joana S. Cristóvão, Urmi Sengupta, Nicha Puangmalai, Ana P. Carapeto, Mário S. Rodrigues, Isabel Cardoso, Güenter Fritz, Federico Herrera, Rakez Kayed, Isabelle Landrieu and Cláudio M. Gomes ()
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Guilherme G. Moreira: Universidade de Lisboa
François-Xavier Cantrelle: CNRS ERL9002 Integrative Structural Biology
Andrea Quezada: Universidade de Lisboa
Filipa S. Carvalho: Universidade de Lisboa
Joana S. Cristóvão: Universidade de Lisboa
Urmi Sengupta: University of Texas Medical Branch
Nicha Puangmalai: University of Texas Medical Branch
Ana P. Carapeto: Universidade de Lisboa
Mário S. Rodrigues: Universidade de Lisboa
Isabel Cardoso: Universidade do Porto
Güenter Fritz: University of Hohenheim
Federico Herrera: Universidade de Lisboa
Rakez Kayed: University of Texas Medical Branch
Isabelle Landrieu: CNRS ERL9002 Integrative Structural Biology
Cláudio M. Gomes: Universidade de Lisboa

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26584-2

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