Glycation Induces Formation of Amyloid Cross-β 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-␤ 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-␤ 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 ␤-sheet conformation, as measured with circular dichroism spectropolarimetry. Moreover, it displays cross-␤ structure, as determined with x-ray fiber diffraction. We conclude that glycation induces refolding of initially globular albumin into amyloid fibrils comprising cross-␤ structure. This would explain how glycated ligands and amyloid ligands can bind to the same multiligand "cross-␤ structure" receptors and to tPA.

Deciphering metal-induced oxidative damages on glycated albumin structure and function

“…The presence of β-amyloid like fibril in CuBSAG or 3ZnBSAG structures could explain their relative cytotoxicity for microglia cells. Several previous studies have already highlighted this β-amyloid cytotoxicity of glycated albumin [8,10]. We can also notice that the partial conversion of secondary structure from α-helix into intramolecular β-sheets is rather promoted by the sole incubation at 37°C than the glycation process.…”

“…Conversely, in the presence of Cu(II) ions, aggregation and glycation appear to be rather competitive processes. If previous studies have demonstrated that aggregation was a process normally associated with glycation [8][9][10], we have also established that glycated albumin loses its capacity to selfassembly into aggregates following thermal process [28].…”

“…Main cellular receptors for AGEs, including RAGE, CD36, MSR-A and MSR-B, are thought to be also primary transporters of amyloid type peptides [6,7]. Besides, protein glycation process could induce the formation of several types of aggregates such as globular forms or amyloid fibrils [8][9][10]. Terminal glycation products are well known to be closely involved in neurodegenerative diseases by promoting amyloid deposit in brain [11].…”

Protection against Advanced Glycation End Products and the Mode of Action of Lemon Balm on Hemoglobin Fructose-Mediated Glycation

“…The reverse effect of LB extract on heme degradation and conformational alteration of Hb originates from its controlling action on the β-amyloid structure formation. A feature of glycated proteins is the propensity to condense into amyloid fibrils, which are characterized by a specific quaternary structure element known as cross-β structure [41]. In contrast to the holo structure, removal of the prosthetic group from many proteins results in apo forms which commonly leads to the formation of the amyloid structure [29].…”

Glycation of antibodies: Modification, methods and potential effects on biological functions

“…[25][26][27][28] AGEs-damaged proteins are highly reactive and become cross-linked, structurally altered, and ultimately aggregated, and these non-native states are toxic for many cell types (e.g., endothelial, neuronal, retinal, leukocytes) and associated with advanced diseases. 29 However, in the manufacturing of therapeutic recombinant antibody products, AGEs formation has not been observed at significant amounts, even with low 21 or high levels of glycation. 8 For therapeutic mAbs, the potential effects of glycation, such as blocking the biologically functional site or further degradation that induces aggregation, make glycation a potential critical quality attribute (CQA).…”