Modeling the Interaction between Quinolinate and the Receptor for Advanced Glycation End Products (RAGE): Relevance for Early Neuropathological Processes

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.

Targeting the Receptor for Advanced Glycation Endproducts (RAGE): A Medicinal Chemistry Perspective

“… e RAGE-Aβ model complex predicted by protein–protein docking software reported in ref ( 83 ). f Binding mode of quinolinic acid and RAGE VC1 domain predicted by computational docking in ref ( 87 ). …”

“… f Binding mode of quinolinic acid and RAGE VC1 domain predicted by computational docking in ref ( 87 ). …”

“… 86 More recently, quinolinic acid has been investigated as a putative endogenous RAGE ligand. 87 , 88 Flexible docking studies with quinolinic acid on human and rat VC1 domains by Serratos and co-workers identified the binding pattern across seven sites, including the CML/CEL and MG-H binding loci. 22 , 26 , 87 Using fluorometric measurements, the K d of quinolinic acid for VC1 was estimated to be approximately 43 nM ( Table 1 ).…”

On the antioxidant, neuroprotective and anti-inflammatory properties of S-allyl cysteine: An update

“…It was concluded that this SAC-related garlic derived compound possesses important antiglycative properties, but once again, this effect deserves additional confirmation in living systems. Supporting evidence on a real protective role of SAC on the AGEPs-related damaging signaling has been recently published by our group through an in vivo approach involving the receptor for AGEPs, RAGEP (Serratos et al, 2015). The dimeric transmembrane RAGEP protein is involved in triggering different signaling cascades leading to cell damage once it is stimulated by AGEPs.…”

Increased flux of the plant sterols campesterol and sitosterol across a disrupted blood brain barrier

“…Rage is a receptor-transporter system that can binds to many ligands and activates many pathways. Disturbances in Rage have been linked to many inflammatory and neurodegenerative disorders like Huntington's disease(Serratos et al, 2015). BBB disruption does not occur in all cases of neurodegeneration.…”