Homodimerization Is Essential for the Receptor for Advanced Glycation End Products (RAGE)-mediated Signal Transduction

Abstract

The receptor for advanced glycation end products (RAGE) is a pattern-recognition receptor that binds to diverse ligands and initiates a downstream proinflammatory signaling cascade. RAGE activation has been linked to diabetic complications, Alzheimer disease, infections, and cancers. RAGE is known to mediate cell signaling and downstream proinflammatory gene transcription activation, although the precise mechanism surrounding receptor-ligand interactions is still being elucidated. Recent fluorescence resonance energy transfer evidence indicates that RAGE may form oligomers on the cell surface and that this could be related to signal transduction. To investigate whether RAGE forms oligomers, protein-protein interaction assays were carried out. Here, we demonstrate the interaction between RAGE molecules via their N-terminal V domain, which is an important region involved in ligand recognition. By protein cross-linking using water-soluble and membrane-impermeable cross-linker bis(sulfosuccinimidyl) suberate and nondenaturing gels, we show that RAGE forms homodimers at the plasma membrane, a process potentiated by S100B and advanced glycation end products. Soluble RAGE, the RAGE inhibitor, is also capable of binding to RAGE, similar to V peptide, as shown by surface plasmon resonance. Incubation of cells with soluble RAGE or RAGE V domain peptide inhibits RAGE dimerization, subsequent phosphorylation of intracellular MAPK proteins, and activation of NF-B pathways. Thus, the data indicate that dimerization of RAGE represents an important component of RAGE-mediated cell signaling.

Neurodegenerative Markers are Increased in Postmortem BA21 Tissue from African Americans with Alzheimer’s Disease

“…Although not statistically significant, levels of the soluble form of RAGE (sRAGE) were decreased 48% in African Americans and indicated a medium effect size. sRAGE lacks the transmembrane domain and intracellular tail and is thought to act as an extracellular decoy by sequestering RAGE ligands [47,[53][54][55]. That sequestration can then prevent the activation of RAGE and its downstream pathological signaling effects.…”

A Soluble Receptor for Advanced Glycation End Product Levels in Patients with Systemic Lupus Erythematosus

“…[18,38] Another possible regulatory route of the sRAGE level is through alternative splicing and proteinases. Zong et al [39] recently proposed that sRAGE might not only function as a 'decoy' to exert its inhibitory effects on RAGE but also act in a more direct way by binding to the cell surface of RAGE to block the formation of homodimers. Hence, the decreased levels of sRAGE could contribute to enhanced RAGE-mediated pro-inflammatory signaling, thus supporting the possibility of the essential role of RAGE in SLE pathology.…”

RAGE and Its Ligands in Melanoma

“…with its ligands have been proposed to reflect the possible RAGE/ligand interactions [39,63,[75][76][77][78][79]. RAGE oligomerization could occur through contacts between the V domain [80], C1 domain [80], [77] or C2 domain, [75,79], in a ligand dependent manner [79].…”