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Modeling the interaction between quinolinate and the receptor for advanced glycation end products (RAGE): relevance
Iris N Serratos1, Pilar Castellanos2, Nina Pastor3
1Departamento de Química, Universidad Autónoma Metropolitana-Iztapalapa, México D.F., México; Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, Manuel Velasco Suárez, SSA, México D.F., México.
Abstract:
The receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor involved in neurodegenerative and inflammatory disorders. RAGE induces cellular signaling upon binding to a variety of ligands. Evidence suggests that RAGE up-regulation is involved in quinolinate (QUIN)-induced toxicity. We investigated the QUIN-induced toxic events associated with early noxious responses, which might be linked to signaling cascades leading to cell death. The extent of early cellular damage caused by this receptor in the rat striatum was characterized by image processing methods. To document the direct interaction between QUIN and RAGE, we determined the binding constant (Kb) of RAGE (VC1 domain) with QUIN through a fluorescence assay. We modeled possible binding sites of QUIN to the VC1 domain for both rat and human RAGE. QUIN was found to bind at multiple sites to the VC1 dimer, each leading to particular mechanistic scenarios for the signaling evoked by QUIN binding, some of which directly alter RAGE oligomerization. This work contributes to the understanding of the phenomenon of RAGE-QUIN recognition, leading to the modulation of RAGE function.
Insights
The receptor for advanced glycation end products (RAGE) binds quinolinate (QUIN), triggering toxic cell signaling. This interaction, involving RAGE
Area of Science:
- Neuroscience
- Molecular Biology
- Toxicology
Background:
- The receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor implicated in neurodegenerative and inflammatory conditions.
- RAGE activation by various ligands initiates cellular signaling pathways.
- Increased RAGE expression is linked to quinolinate (QUIN)-induced neurotoxicity.
Purpose of the Study:
- To investigate the early toxic events and signaling cascades induced by QUIN, potentially leading to cell death.
- To characterize the extent of early cellular damage in the rat striatum mediated by RAGE.
- To elucidate the direct molecular interaction between QUIN and RAGE.
Main Methods:
- Image processing techniques were employed to quantify early cellular damage in the rat striatum.
- Fluorescence assays were used to determine the binding constant (Kb) between the RAGE VC1 domain and QUIN.
- Molecular modeling was utilized to predict binding sites of QUIN within the RAGE VC1 domain for both rat and human RAGE.
Main Results:
- QUIN was observed to bind to multiple sites on the RAGE VC1 dimer.
- These binding interactions suggest distinct mechanistic pathways for QUIN-induced signaling.
- Some binding events were found to directly alter RAGE oligomerization, impacting receptor function.
Conclusions:
- This study clarifies the molecular recognition between RAGE and QUIN.
- The findings reveal how QUIN binding modulates RAGE function through altered oligomerization and signaling.
- Understanding RAGE-QUIN interactions is crucial for developing therapeutic strategies against neurotoxicity.
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