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

Autor: Urmi Sengupta, Guilherme G. Moreira, Ana P. Carapeto, Filipa S. Carvalho, Andrea Quezada, Mário Rodrigues, Isabel Cardoso, Guenter Fritz, Nicha Puangmalai, Isabelle Landrieu, Federico Herrera, Rakez Kayed, Cláudio M. Gomes, Joana S. Cristóvão, François Xavier Cantrelle
Přispěvatelé: Universidade de Lisboa = University of Lisbon (ULISBOA), Biologie Structurale Intégrative (ERL 9002 - BSI ), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), The University of Texas Medical Branch (UTMB), Universidade do Porto = University of Porto, Instituto de Ciências Biomédicas de Abel Salazar (ICBAS), University of Hohenheim, This work was funded by Fundação para a Ciência e Tecnologia (Portugal) through research grants PTDC/NEU-NMC/2138/2014 (to C.M.G.), PTDC/BIA-BQM/29963/2017 (F.S.C.), PTDC/MED-NEU/31417/2017 (to F.H.), and POCI-01-0145-FEDER-007274 (to I.C.), investigator grants CEECIND/00031/2017 (to A.P.C.) and IF/00094/2013/CP1173/CT0005 (to F.H.), PhD fellowship SFRH/BD/101171/2014 (to J.S.C.) and DFA/BD/6443/2020 (to G.G.M.), and center grants UIDB/04046/2020 and UID/MULTI/04046/2020 (to BioISI) and Norte-01-0145-FEDER-000008 (to IBMC/I3S)., Landrieu, Isabelle, Universidade de Lisboa (ULISBOA), Universidade do Porto
Jazyk: angličtina
Rok vydání: 2021
Předmět:
[SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry
Molecular Biology/Structural Biology [q-bio.BM]
Science
Tau protein
General Physics and Astronomy
tau Proteins
S100 Calcium Binding Protein beta Subunit
Protein Aggregation
Pathological
Article
Biophysical Phenomena
General Biochemistry
Genetics and Molecular Biology
Cell Line
03 medical and health sciences
0302 clinical medicine
Microtubule
Biophysical chemistry
Calcium-binding protein
mental disorders
Humans
Protein folding
[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biochemistry [q-bio.BM]
Nuclear Magnetic Resonance
Biomolecular
[SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biochemistry [q-bio.BM]
030304 developmental biology
0303 health sciences
Multidisciplinary
biology
[SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Structural Biology [q-bio.BM]
Chemistry
Neurodegenerative Diseases
General Chemistry
Kinetics
Proteostasis
Structural biology
Chaperone (protein)
biology.protein
Biophysics
Protein Structural Elements
030217 neurology & neurosurgery
Molecular Chaperones
Protein Binding
Binding domain
Zdroj: Nature Communications, Vol 12, Iss 1, Pp 1-16 (2021)
Nature Communications
Nature Communications, 2021, 12 (1), pp.6292. ⟨10.1038/s41467-021-26584-2⟩
Nature Communications, Nature Publishing Group, 2021, 12 (1), pp.6292. ⟨10.1038/s41467-021-26584-2⟩
ISSN: 2041-1723
DOI: 10.1038/s41467-021-26584-2⟩
Popis: 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.
The calcium binding protein S100B is an abundantly expressed protein in the brain and has neuro-protective functions by inhibiting Aβ aggregation and metal ion toxicity. Here, the authors combine cell biology and biochemical experiments with chemical kinetics and NMR measurements and show that S100B protein is an extracellular Tau chaperone and further characterize the interactions between S100B and Tau.
Databáze: OpenAIRE
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