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

DOI: 10.1038/s41467-021-26584-2 DOI Help

Authors: Guilherme G. Moreira (Universidade de Lisboa) , François-Xavier Cantrelle (CNRS ERL9002 Integrative Structural Biology; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille) , 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; Instituto de Ciências Biomédicas Abel Salazar (ICBAS)) , Guenter Fritz (University of Hohenheim) , Federico Herrera (Universidade de Lisboa) , Rakez Kayed (University of Texas Medical Branch) , Isabelle Landrieu (CNRS ERL9002 Integrative Structural Biology; Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Risk Factors and Molecular Determinants of Aging-Related Diseases) , Cláudio M. Gomes (Universidade de Lisboa)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 12

State: Published (Approved)
Published: November 2021
Diamond Proposal Number(s): 27184

Open Access Open Access

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.

Diamond Keywords: Alzheimer's Disease

Subject Areas: Biology and Bio-materials, Chemistry


Instruments: B21-High Throughput SAXS

Added On: 08/11/2021 09:18

Documents:
s41467-021-26584-2.pdf

Discipline Tags:

Neurodegenerative Diseases Non-Communicable Diseases Health & Wellbeing Biochemistry Neurology Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Scattering Small Angle X-ray Scattering (SAXS)