Structural basis for pattern recognition by the receptor for advanced glycation end products (RAGE).
The receptor for advanced glycated end products (RAGE) is a multiligand receptor that is implicated in the pathogenesis of various diseases, including diabetic complications, neurodegenerative disorders, and inflammatory responses. The ability of RAGE to recognize advanced glycated end products (AGEs) formed by nonenzymatic glycoxidation of cellular proteins places RAGE in the category of pattern recognition receptors. The structural mechanism of AGE recognition was an enigma due to the diversity of chemical structures found in AGE-modified proteins. Here, using NMR spectroscopy we showed that the immunoglobulin V-type domain of RAGE is responsible for recognizing various classes of AGEs. Three distinct surfaces of the V domain were identified to mediate AGE-V domain interactions. They are located in the positively charged areas of the V domain. The first interaction surface consists of strand C and loop CC ', the second interaction surface consists of strand C ', strand F, and loop FG, and the third interaction surface consists of strand A ' and loop EF. The secondary structure elements of the interaction surfaces exhibit significant flexibility on the ms-micros time scale. Despite highly specific AGE-V domain interactions, the binding affinity of AGEs for an isolated V domain is low, approximately 10 microm. Using in-cell fluorescence resonance energy transfer we show that RAGE is a constitutive oligomer on the plasma membrane. We propose that constitutive oligomerization of RAGE is responsible for recognizing patterns of AGE-modified proteins with affinities less than 100 nm.
Xie
Jingjing
J
Department of Chemistry State University of New York, Albany, New York 12222, USA.
Reverdatto
Sergey
S
Frolov
Andrej
A
Hoffmann
Ralf
R
Burz
David S
DS
Shekhtman
Alexander
A
D002460:Cell Line; D048909:Diabetes Complications / Q000235:genetics / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D020836:Protein Structure, Quaternary / Q000235:genetics; D017433:Protein Structure, Secondary / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D000067759:Receptor for Advanced Glycation End Products / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products