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Functional modulation of RAGE activation by multimeric S100B using single-domain antibodies
Margarida C Simões1, Joana S Cristóvão1, Els Pardon2
1BioISI - Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal; Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal.
The Journal of Biological Chemistry
|November 14, 2024
Summary
Researchers developed nanobodies (Nbs) that target S100B protein oligomers, effectively blocking its interaction with RAGE. This discovery offers new tools for studying S100B functions and potential therapeutic strategies.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- S100B protein is crucial for brain cell functions, exhibiting both neurotrophic and neurotoxic effects mediated by RAGE.
- S100B exists in various oligomeric forms, influencing its biological activity and interaction with RAGE.
Purpose of the Study:
- To discover and characterize nanobodies (Nbs) that target dimeric and tetrameric S100B.
- To modulate S100B-mediated activation of the receptor for advanced glycation end products (RAGE).
Main Methods:
- Biolayer interferometry (BLI) for high-affinity binding analysis.
- Size-exclusion chromatography for stable complex formation.
- Structural and docking analyses to identify binding sites.
- Cell-based assays (SH-SY5Y cells) to assess RAGE-mediated activity modulation.
Main Results:
- Two Nbs demonstrated high-affinity binding to tetrameric S100B.
- Nbs bind to S100B regions critical for RAGE interaction.
- Nbs successfully modulated S100B's RAGE-mediated neurotrophic activity in cell assays.
- BLI competition assays confirmed selective blockade of S100B-RAGE engagement.
Conclusions:
- Nanobodies are effective tools for modulating S100B and RAGE interactions.
- These Nbs can elucidate molecular and cellular mechanisms involving S100B.
- The findings suggest potential therapeutic applications for targeting S100B-RAGE pathways.
