title: Glycation induces formation of amyloid cross-beta structure in albumin.
abstract: Amyloid fibrils are components of proteinaceous plaques that are associated with conformational diseases such as Alzheimer's disease, transmissible spongiform encephalopathies, and familial amyloidosis. Amyloid polypeptides share a specific quarternary structure element known as cross-beta structure. Commonly, fibrillar aggregates are modified by advanced glycation end products (AGE). In addition, AGE formation itself induces protein aggregation. Both amyloid proteins and protein-AGE adducts bind multiligand receptors, such as receptor for AGE, CD36, and scavenger receptors A and B type I, and the serine protease tissue-type plasminogen activator (tPA). Based on these observations, we hypothesized that glycation induces refolding of globular proteins, accompanied by formation of cross-beta structure. Using transmission electron microscopy, we demonstrate here that glycated albumin condensates into fibrous or amorphous aggregates. These aggregates bind to amyloid-specific dyes Congo red and thioflavin T and to tPA. In contrast to globular albumin, glycated albumin contains amino acid residues in beta-sheet conformation, as measured with circular dichroism spectropolarimetry. Moreover, it displays cross-beta structure, as determined with x-ray fiber diffraction. We conclude that glycation induces refolding of initially globular albumin into amyloid fibrils comprising cross-beta structure. This would explain how glycated ligands and amyloid ligands can bind to the same multiligand "cross-beta structure" receptors and to tPA.
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Barend
authors.initials: B
authors.lastname: Bouma
authors.forename: Loes M J
authors.initials: LM
authors.lastname: Kroon-Batenburg
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Wu
authors.forename: Bettina
authors.initials: B
authors.lastname: Brünjes
authors.forename: George
authors.initials: G
authors.lastname: Posthuma
authors.forename: Onno
authors.initials: O
authors.lastname: Kranenburg
authors.forename: Philip G
authors.initials: PG
authors.lastname: de Groot
authors.forename: Emile E
authors.initials: EE
authors.lastname: Voest
authors.forename: Martijn F B G
authors.initials: MF
authors.lastname: Gebbink
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D052160:Benzothiazoles; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D003224:Congo Red; D019281:Dimerization; D017127:Glycation End Products, Advanced / Q000737:chemistry / Q000494:pharmacology; D006031:Glycosylation; D051379:Mice; D008854:Microscopy, Electron; D011489:Protein Denaturation; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D012709:Serum Albumin / Q000737:chemistry* / Q000378:metabolism*; D013844:Thiazoles; D010959:Tissue Plasminogen Activator / Q000378:metabolism
chemical_list: D000682:Amyloid; D052160:Benzothiazoles; D017127:Glycation End Products, Advanced; D012709:Serum Albumin; D013844:Thiazoles; C009462:thioflavin T; D003224:Congo Red; D010959:Tissue Plasminogen Activator