title: Glycine residues appear to be evolutionarily conserved for their ability to inhibit aggregation.
abstract: Six glycine residues of human muscle acylphosphatase (AcP) are evolutionarily conserved across the three domains of life. We have generated six variants of AcP, each having a glycine substituted by an alanine (G15A, G19A, G37A, G45A, G53A, and G69A). Three additional variants had Gly45 replaced by serine, glutamate, and arginine, respectively. The mutational variants do not, on average, have a lower conformational stability than other variants with substitutions of nonconserved residues. In addition, only the G15A variant is enzymatically inactive. However, all variants, with the exception of the G15A mutant, form amyloid aggregates more rapidly than the wild-type. Dynamic light-scattering experiments carried out under conditions close to physiological confirm that aggregate formation is generally more pronounced for the glycine-substituted variants. Apart from the glycine at position 15, all other conserved glycine residues in this protein could have been maintained during evolution because of their ability to inhibit aggregation.
authors.affiliation: Dipartimento di Scienze Biochimiche, Università degli Studi di Firenze, Viale Morgagni 50, 50134 Firenze, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Parrini
authors.forename: Niccolò
authors.initials: N
authors.lastname: Taddei
authors.forename: Matteo
authors.initials: M
authors.lastname: Ramazzotti
authors.forename: Donatella
authors.initials: D
authors.lastname: Degl'Innocenti
authors.forename: Giampietro
authors.initials: G
authors.lastname: Ramponi
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Chiti
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000235:genetics / Q000502:physiology*; D000595:Amino Acid Sequence; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D017124:Conserved Sequence; D004795:Enzyme Stability / Q000235:genetics; D019143:Evolution, Molecular; D005998:Glycine / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009132:Muscles / Q000201:enzymology; D017434:Protein Structure, Tertiary; D000097024:Acylphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D000682:Amyloid; D005998:Glycine; D000097024:Acylphosphatase