Structural insights into the oligomerization mode of the human receptor for advanced glycation end-products

Area of Science:

• Structural biology
• Molecular and cellular biology
• Biochemistry

Background:

• The receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor implicated in various diseases, including diabetes, vascular complications, Alzheimer's disease, and cancer.
• RAGE signaling is triggered by diverse ligands and involves receptor oligomerization, which is critical for forming active signaling complexes.
• The precise mode of RAGE oligomerization in response to different ligands remains unclear.

Purpose of the Study:

• To elucidate the structural basis of RAGE oligomerization and its role in ligand binding and signaling.
• To provide the first crystal structure of the VC1C2 fragment of the RAGE ectodomain.
• To investigate potential dimerization modes of RAGE, including ectodomain association and transmembrane domain interactions.

Main Methods:

• X-ray crystallography was employed to determine the structures of the RAGE VC1C2 and VC1 fragments.
• Analysis of crystal packing to identify intermolecular contacts and potential oligomerization interfaces.
• Homology modeling based on known transmembrane receptors to infer dimerization mechanisms.

Main Results:

• The crystal structure of the RAGE VC1C2 fragment reveals the C2 domain's conformational flexibility relative to the VC1 tandem.
• Crystal packing analysis indicates RAGE homodimerization through V domain contacts in the ectodomain.
• A conserved GxxxG motif in the transmembrane domain suggests a potential dimerization interface.

Conclusions:

• RAGE exhibits a multimodal homodimerization strategy involving both ectodomain and transmembrane domain interactions.
• This proposed dimerization mechanism provides a structural basis for ligand-specific complex formation and RAGE-mediated signaling.
• RAGE homodimerization is critical for its role in disease progression and cell adhesion.