RAGE and amyloid beta interactions: atomic force microscopy and molecular modeling.
In the AD brain, there are elevated amounts of soluble and insoluble Abeta peptides which enhance the expression of membrane bound and soluble receptor for advanced glycation end products (RAGE). The binding of soluble Abeta to soluble RAGE inhibits further aggregation of Abeta peptides, while membrane bound RAGE-Abeta interactions elicit activation of the NF-kappaB transcription factor promoting sustained chronic neuroinflammation. Atomic force microscopy observations demonstrated that the N-terminal domain of RAGE, by interacting with Abeta, is a powerful inhibitor of Abeta polymerization even at prolonged periods of incubation. Hence, the potential RAGE-Abeta structural interactions were further explored utilizing a series of computational chemistry algorithms. Our modeling suggests that a soluble dimeric RAGE assembly creates a positively charged well into which the negative charges of the N-terminal domain of dimeric Abeta dock.
Chaney
Michael O
MO
Department of Surgery, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
Stine
W Blaine
WB
Kokjohn
Tyler A
TA
Kuo
Yu-Min
YM
Esh
Chera
C
Rahman
Afroza
A
Luehrs
Dean C
DC
Schmidt
Ann Marie
AM
Stern
David
D
Yan
Shi Du
SD
Roher
Alex E
AE
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D019281:Dimerization; D004220:Disulfides / Q000737:chemistry; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D018625:Microscopy, Atomic Force; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D012995:Solubility
D016229:Amyloid beta-Peptides; D004220:Disulfides; D017127:Glycation End Products, Advanced; D007074:Immunoglobulin G; D010446:Peptide Fragments; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C075222:amyloid beta-protein (1-42)