The receptor for advanced glycation end products (RAGE) specifically recognizes methylglyoxal-derived AGEs.
Diabetes-induced hyperglycemia increases the extracellular concentration of methylglyoxal. Methylglyoxal-derived hydroimidazolones (MG-H) form advanced glycation end products (AGEs) that accumulate in the serum of diabetic patients. The binding of hydroimidozolones to the receptor for AGEs (RAGE) results in long-term complications of diabetes typified by vascular and neuronal injury. Here we show that binding of methylglyoxal-modified albumin to RAGE results in signal transduction. Chemically synthesized peptides containing hydroimidozolones bind specifically to the V domain of RAGE with nanomolar affinity. The solution structure of an MG-H1-V domain complex revealed that the hydroimidazolone moiety forms multiple contacts with a positively charged surface on the V domain. The high affinity and specificity of hydroimidozolones binding to the V domain of RAGE suggest that they are the primary AGE structures that give rise to AGEs-RAGE pathologies.
Department of Chemistry, State University of New York at Albany , Albany, New York 12222, United States.
Jing
J
Xue
Rashmi
R
Ray
David
D
Singer
David
D
Böhme
David S
DS
Burz
Vivek
V
Rai
Ralf
R
Hoffmann
Alexander
A
Shekhtman
D002460:Cell Line; D017127:Glycation End Products, Advanced / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011765:Pyruvaldehyde / Q000737:chemistry* / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D011765:Pyruvaldehyde