TY - JOUR
T1 - Dynamic interactions and Ca2+-binding modulate the holdase-type chaperone activity of S100B preventing tau aggregation and seeding
AU - Moreira, Guilherme G.
AU - Cantrelle, François Xavier
AU - Quezada, Andrea
AU - Carvalho, Filipa S.
AU - Cristóvão, Joana S.
AU - Sengupta, Urmi
AU - Puangmalai, Nicha
AU - Carapeto, Ana P.
AU - Rodrigues, Mário S.
AU - Cardoso, Isabel
AU - Fritz, Güenter
AU - Herrera, Federico
AU - Kayed, Rakez
AU - Landrieu, Isabelle
AU - Gomes, Cláudio M.
N1 - Funding Information:
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). We acknowledge the FCUL Microscopy Facility and the i3S Scientific Platform Histology and electron microscopy (HEMS), members of the national infrastructure PPBI—Portuguese Platform of Bioimaging (PPBI-POCI-01-0145-FEDER-022122), and Lille NMR facilities, funded by the Nord Region Council, CNRS, Pasteur Institute of Lille, European Community (FEDER), French Research Ministry, and Univ. Lille. The excellent support by staff of beamline B21 at Diamond Light Source is gratefully acknowledged. This work benefited from access to B21 at Diamond Light Source and has been supported by iNEXT-Discovery, project number 871037, funded by the Horizon 2020 program of the European Commission. This study was also supported through grants from TGE RMN THC (FR-3050, France), LabEx (Laboratory of Excellence) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to Alzheimer’s disease) (to I.L.). We thank Dr E. Dupré and Mme J. Mortelecque for support in NMR experiments. A. Figueira is gratefully acknowledged for support in preparation of Aβ42, and Dr. B. Victor for assistance with Pymol Scripting. Bial Foundation through grant PT/FB/BL-2014-343 (to C.M.G.), NIH grants R01 AG054025 and R01 NS094557 (to R.K.) and CONACYT-Mexico (CVU 298418) and Científicæs Mexicanæs en el Extranjero (to A.Q.).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85118437711&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-26584-2
DO - 10.1038/s41467-021-26584-2
M3 - Article
C2 - 34725360
AN - SCOPUS:85118437711
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 6292
ER -