Glycine Residues Appear to Be Evolutionarily Conserved for Their Ability to Inhibit Aggregation

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 s...

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Bibliographic Details
Published in:Structure (London) 2005-08, Vol.13 (8), p.1143-1151
Main Authors: Parrini, Claudia, Taddei, Niccolò, Ramazzotti, Matteo, Degl’Innocenti, Donatella, Ramponi, Giampietro, Dobson, Christopher M., Chiti, Fabrizio
Format: Article
Language:English
Subjects:
Acid Anhydride Hydrolases - genetics
Acid Anhydride Hydrolases - physiology
Acylphosphatase
Amino Acid Sequence
Amyloid - antagonists & inhibitors
Amyloid - chemistry
Amyloid - genetics
Conserved Sequence
Enzyme Stability - genetics
Evolution, Molecular
Glycine - genetics
Glycine - physiology
Humans
Muscles - enzymology
Protein Structure, Tertiary
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Summary: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.
ISSN:0969-2126
1878-4186
DOI:10.1016/j.str.2005.04.022