title: Stabilization of a native protein mediated by ligand binding inhibits amyloid formation independently of the aggregation pathway.
abstract: The acylphosphatases from Sulfolobus solfataricus and Drosophila melanogaster (Sso AcP and AcPDro2) were previously shown to form amyloid-like aggregates without the need to unfold initially. Inorganic phosphate (Pi), a competitive inhibitor binding specifically to the active site of these proteins, was found to stabilize, upon binding, the native state of AcPDro2 and to inhibit its conversion into amyloid-like fibrils. The inhibitory effect of Pi is suppressed only in a variant in which the Arg residue responsible for Pi binding is mutated. The study on Sso AcP shows that Pi retards both the formation of the initial nativelike oligomers and their subsequent conversion into protofibrils. Thus, stabilization of the native structure mediated by specific binding with small molecules can be an effective therapeutic strategy against protein deposition diseases that originate from initially folded proteins, independently of the structure of the protein, its aggregation pathway, and the particular aggregated species responsible for pathogenesis.
authors.affiliation: Dipartimento di Scienze Biochimiche, Università di Firenze, Viale Morgagni 50, 50134 Firenze, Italy.
authors.forename: Gemma
authors.initials: G
authors.lastname: Soldi
authors.forename: Georgia
authors.initials: G
authors.lastname: Plakoutsi
authors.forename: Niccolo
authors.initials: N
authors.lastname: Taddei
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Chiti
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D000682:Amyloid / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000818:Animals; D002384:Catalysis; D004331:Drosophila melanogaster / Q000201:enzymology; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D010710:Phosphates / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D048229:Sulfolobus solfataricus / Q000201:enzymology; D000097024:Acylphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D000682:Amyloid; D008024:Ligands; D010710:Phosphates; D000097024:Acylphosphatase