The distribution of residues in a polypeptide sequence is a determinant of aggregation optimized by evolution.
It has been shown that the propensity of a protein to form amyloid-like fibrils can be predicted with high accuracy from the knowledge of its amino acid sequence. It has also been suggested, however, that some regions of the sequences are more important than others in determining the aggregation process. Here, we have addressed this issue by constructing a set of "sequence scrambled" variants of the first 29 residues of horse heart apomyoglobin (apoMb(1-29)), in which the sequence was modified while maintaining the same amino acid composition. The clustering of the most amyloidogenic residues in one region of the sequence was found to cause a marked increase of the elongation rate (k(agg)) and a remarkable shortening of the lag phase (t(lag)) of the fibril growth, as determined by far-UV circular dichroism and thioflavin T fluorescence. We also show that taking explicitly into consideration the presence of aggregation-promoting regions in the predictive methods results in a quantitative agreement between the theoretical and observed k(agg) and t(lag) values of the apoMb(1-29) variants. These results, together with a comparison between homologous segments from the family of globins, indicate the existence of a negative selection against the clustering of highly amyloidogenic residues in one or few regions of polypeptide sequences.
Monsellier
Elodie
E
Dipartimento di Scienze Biochimiche, Università degli studi di Firenze, Florence, Italy.
Ramazzotti
Matteo
M
de Laureto
Patrizia Polverino
PP
Tartaglia
Gian-Gaetano
GG
Taddei
Niccolò
N
Fontana
Angelo
A
Vendruscolo
Michele
M
Chiti
Fabrizio
F
D000595:Amino Acid Sequence; D001059:Apoproteins / Q000737:chemistry* / Q000235:genetics* / Q000648:ultrastructure; D003198:Computer Simulation; D019143:Evolution, Molecular; D008956:Models, Chemical; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009211:Myoglobin / Q000737:chemistry* / Q000235:genetics* / Q000648:ultrastructure; D010455:Peptides / Q000737:chemistry; D020539:Sequence Analysis, Protein / Q000379:methods*; D013329:Structure-Activity Relationship
D001059:Apoproteins; D009211:Myoglobin; D010455:Peptides; C010857:apomyoglobin