title: Kinetic partitioning of protein folding and aggregation.
abstract: We have systematically studied the effects of 40 single point mutations on the conversion of the denatured form of the alpha/beta protein acylphosphatase (AcP) into insoluble aggregates. All the mutations that significantly perturb the rate of aggregation are located in two regions of the protein sequence, residues 16-31 and 87-98, each of which has a relatively high hydrophobicity and propensity to form beta-sheet structure. The measured changes in aggregation rate upon mutation correlate with changes in the hydrophobicity and beta-sheet propensity of the regions of the protein in which the mutations are located. The two regions of the protein sequence that determine the aggregation rate are distinct from those parts of the sequence that determine the rate of protein folding. Dissection of the protein into six peptides corresponding to different regions of the sequence indicates that the kinetic partitioning between aggregation and folding can be attributed to the intrinsic conformational preferences of the denatured polypeptide chain.
authors.affiliation: Dipartimento di Scienze Biochimiche, Università degli Studi di Firenze, Viale Morgagni 50, 50134 Firenze, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Chiti
authors.forename: Niccolò
authors.initials: N
authors.lastname: Taddei
authors.forename: Fabiana
authors.initials: F
authors.lastname: Baroni
authors.forename: Cristina
authors.initials: C
authors.lastname: Capanni
authors.forename: Massimo
authors.initials: M
authors.lastname: Stefani
authors.forename: Giampietro
authors.initials: G
authors.lastname: Ramponi
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D052160:Benzothiazoles; D002850:Chromatography, Gel; D002942:Circular Dichroism; D005453:Fluorescence; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009132:Muscles / Q000201:enzymology*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics; D011485:Protein Binding; D011489:Protein Denaturation; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D012995:Solubility; D013844:Thiazoles / Q000378:metabolism; D000097024:Acylphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D052160:Benzothiazoles; D010446:Peptide Fragments; D013844:Thiazoles; D000097024:Acylphosphatase; C009462:thioflavin T