The neuronal S100B protein is a calcium-tuned suppressor of amyloid- aggregation
| العنوان: | The neuronal S100B protein is a calcium-tuned suppressor of amyloid- aggregation |
|---|---|
| المؤلفون: | Katrin Kierdorf, Bernd Reif, Vanessa K. Morris, Joana S. Cristóvão, Tobias Madl, Sónia S. Leal, Christoph Göbl, Mobina Alemi, Cláudio M. Gomes, Isabel Cardoso, Günter Fritz, Rodrigo David, Javier Martínez, Hugo M. Botelho |
| المساهمون: | Instituto de Investigação e Inovação em Saúde |
| المصدر: | Repositório Científico de Acesso Aberto de Portugal Repositório Científico de Acesso Aberto de Portugal (RCAAP) instacron:RCAAP Science Advances Sci. Adv. 4:eaaq1702 (2018) |
| بيانات النشر: | American Association for the Advancement of Science, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Amyloid beta-Peptides / metabolismo, Models, Molecular, Amyloid, Neurons / metabolismo, S100 Calcium Binding Protein beta Subunit / metabolism, Protein Conformation, Plasma protein binding, S100 Calcium Binding Protein beta Subunit, Protein aggregation, Fibril, Protein Aggregation, Pathological, Biochemistry, Models, Biological, S100 Calcium Binding Protein beta Subunit / chemistry, 03 medical and health sciences, Protein Aggregates, Structure-Activity Relationship, 0302 clinical medicine, Protein structure, medicine, Humans, Protein Interaction Domains and Motifs, Senile plaques, Neuroinflammation, Research Articles, Neurons, Multidisciplinary, Amyloid beta-Peptides, Amyloid beta-Peptides / chemistry, Chemistry, Protein Aggregation, Pathological / metabolismo, Neurodegeneration, SciAdv r-articles, medicine.disease, 3. Good health, Transport protein, Calcium / metabolismo, Protein Transport, 030104 developmental biology, Amyloid / metabolismo, Biophysics, Calcium, Protein Multimerization, 030217 neurology & neurosurgery, Research Article, Neuroscience, Protein Binding |
| الوصف: | A novel role for S100B, a recognized brain distress marker, as a chaperone-like suppressor of Aβ42 aggregation and toxicity. 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. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::66271798d03e8a55cd1b22b18809e80bTest https://hdl.handle.net/10216/127409Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....66271798d03e8a55cd1b22b18809e80b |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |