Glycosaminoglycans (GAGs) suppress the toxicity of HypF-N prefibrillar aggregates.
A group of diverse human pathologies is associated with proteins unable to retain their native state and convert into prefibrillar and fibrillar amyloid aggregates that are then deposited in the extracellular space. Glycosaminoglycans (GAGs) have been found to physically associate with these deposits and also to promote their formation in vitro. However, the effect of GAGs on the toxicity of these aggregates has been investigated in only one protein system, the amyloid β peptide associated with Alzheimer's disease. In this study, we investigate whether GAGs affect the toxicity of the N-terminal domain of Escherichia coli HypF (HypF-N) oligomers on Chinese hamster ovarian cells and the mechanism by which such suppression is mediated. The results show that heparin and other GAGs inhibit the toxicity observed by HypF-N oligomers in a dose-dependent manner. GAGs were not found to bind preformed HypF-N oligomers, change their morphological and structural characteristics or disaggregate them. Nevertheless, they were found to bind to the cells' surface and prevent the interaction of the oligomers with the cells. Overall, the results indicate that GAGs have a generic ability to inhibit the toxicity of aberrant protein oligomers and that such toxicity suppression can occur through different mechanisms, such as through binding to the oligomers with consequent loss of interaction of the oligomers to the GAGs present on the cell surface, as proposed previously for amyloid β aggregates, or through mechanisms independent of direct GAG-oligomer binding, as shown here for HypF-N aggregates.
Department of Biochemical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
Theodora
T
Saridaki
Mariagioia
M
Zampagni
Benedetta
B
Mannini
Elisa
E
Evangelisti
Niccolò
N
Taddei
Cristina
C
Cecchi
Fabrizio
F
Chiti
D000682:Amyloid / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D016466:CHO Cells; D019878:Carboxyl and Carbamoyl Transferases / Q000378:metabolism* / Q000633:toxicity; D006224:Cricetinae; D003412:Cricetulus; D004926:Escherichia coli / Q000737:chemistry; D029968:Escherichia coli Proteins / Q000378:metabolism* / Q000633:toxicity; D006025:Glycosaminoglycans / Q000378:metabolism*; D011489:Protein Denaturation; D055503:Protein Multimerization
D000682:Amyloid; D029968:Escherichia coli Proteins; D006025:Glycosaminoglycans; D019878:Carboxyl and Carbamoyl Transferases; C504838:hypF protein, E coli