BIBLIOS

Document type
Journal articles

Document subtype
Full paper

Title
The neuronal S100B protein is a calcium-tuned suppressor of amyloid-? aggregation

Participants in the publication
Joana S. Cristóvão (Author)
BioISI - Biosystems & Integrative Sciences Institute
Vanessa K. Morris (Author)
Isabel Cardoso (Author)
Sónia S. Leal (Author)
BioISI - Biosystems & Integrative Sciences Institute
Javier Martínez (Author)
BioISI - Biosystems & Integrative Sciences Institute
Hugo M. Botelho (Author)
Christoph Göbl (Author)
Rodrigo David (Author)
Katrin Kierdorf (Author)
Mobina Alemi (Author)
Tobias Madl (Author)
Günter Fritz (Author)
Bernd Reif (Author)
Cláudio M. Gomes (Author)
Dep. Química e Bioquímica
BioISI

Summary
Amyloid-β (Aβ) aggregation and neuroinflammation are consistent features in Alzheimer’s disease (AD) and strong candidates for the initiation of neurodegeneration. S100B is one of the most abundant proinflammatory proteins that is chronically up-regulated in AD and is found associated with senile plaques. This recognized biomarker for brain distress may, thus, play roles in amyloid aggregation which remain to be determined. We report a novel role for the neuronal S100B protein as suppressor of Aβ42 aggregation and toxicity. We determined the structural details of the interaction between monomeric Aβ42 and S100B, which is favored by calcium binding to S100B, possibly involving conformational switching of disordered Aβ42 into an α-helical conformer, which locks aggregation. From nuclear magnetic resonance experiments, we show that this dynamic interaction occurs at a promiscuous peptide-binding region within the interfacial cleft of the S100B homodimer. This physical interaction is coupled to a functional role in the inhibition of Aβ42 aggregation and toxicity and is tuned by calcium binding to S100B. S100B delays the onset of Aβ42 aggregation by interacting with Aβ42 monomers inhibiting primary nucleation, and the calcium-bound state substantially affects secondary nucleation by inhibiting fibril surface–catalyzed reactions through S100B binding to growing Aβ42 oligomers and fibrils. S100B protects cells from Aβ42-mediated toxicity, rescuing cell viability and decreasing apoptosis induced by Aβ42 in cell cultures. Together, our findings suggest that molecular targeting of S100B could be translated into development of novel approaches to ameliorate AD neurodegeneration.


Institution
BioISI - Biosystems & Integrative Sciences Institute

Where published
Science Advances

Publication Identifiers
ISSN - 2375-2548

Publisher
American Association for the Advancement of Science (AAAS)



Document Identifiers
URL - http://dx.doi.org/10.1126/sciadv.aaq1702
DOI - https://doi.org/10.1126/sciadv.aaq1702

Rankings
Web Of Science Q1 (2018) - 12.804 - MULTIDISCIPLINARY SCIENCES - SCIE