Cysteine mediated disulfide bond formation in RAGE V domain facilitates its functionally relevant dimerization

Area of Science:

• Biochemistry
• Cell Biology
• Molecular Medicine

Background:

• Receptor for Advanced Glycation End product (RAGE) is a multiligand receptor involved in numerous diseases, including diabetes, atherosclerosis, cancer, and neurological disorders.
• Extracellular RAGE comprises V, C1, and C2 domains.

Purpose of the Study:

• To investigate the functional implications of RAGE dimerization.
• To understand how the dimeric state of RAGE influences its interaction with ligands and subsequent cellular responses.

Main Methods:

• Investigated the existence of RAGE as a monomer-ligand equilibrium with a covalently linked dimer form via the V domain.
• Assessed the binding capacity and functional potential of RAGE dimers compared to monomers using advanced glycation end products (AGEs).

Main Results:

• RAGE exists in equilibrium between monomeric and dimeric forms, linked via cysteine in the V domain.
• The dimeric form of RAGE exhibits enhanced binding to AGEs.
• Dimeric RAGE demonstrates increased ERK phosphorylation, cytokine release, and actin polymerization compared to the monomeric form.

Conclusions:

• The dimeric state of RAGE is a key regulator of its function and ligand-mediated signaling.
• RAGE dimerization plays a significant role in the pathogenesis of various RAGE-mediated diseases.