Molecular mechanism of the inhibition of cytochrome c aggregation by Phe-Gly.
Experimental and computational studies suggest that few general principles govern protein/protein interactions and aggregation. The knowledge of these rules may be exploited to design peptides that are able to interfere with the self-assembly and aggregation of proteins. This work is aimed to verify the validity of this hypothesis by investigating the interaction of cytochrome c with Phe and Gly amino acids, Ala-His (carnosine), and two water-soluble dipeptides Phe-Gly and Gly-Phe. The combined use of (1)H NMR, MD, and DSC has shown that: (i) at neutral pH, only Phe-Gly is able to prevent the thermally induced aggregation of cytochrome c; (ii) Phe-Gly interacts with Gly45 and Phe46 residues of the protein, either when the protein is in the folded or in the unfolded state; and (iii) the interaction of Phe-Gly with cytochrome c is sequence-dependent. These results support the hypothesis that the basic principles that describe protein aggregation can be used for the design of peptides with antiaggregating properties.
La Rosa
Carmelo
C
Dipartimento di Scienze Chimiche, Universita' di Catania, V.le A. Doria 6, 95125 Catania, Italy.
Milardi
Danilo
D
Amato
Emanuela
E
Pappalardo
Matteo
M
Grasso
Domenico
D
D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D045304:Cytochromes c / Q000032:analysis / Q000037:antagonists & inhibitors / Q000737:chemistry*; D004151:Dipeptides / Q000032:analysis / Q000737:chemistry*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000032:analysis / Q000737:chemistry; D005998:Glycine / Q000032:analysis / Q000737:chemistry; D006736:Horses; D008956:Models, Chemical; D008958:Models, Molecular; D009038:Motion; D046912:Multiprotein Complexes / Q000032:analysis / Q000737:chemistry; D009206:Myocardium / Q000201:enzymology; D010649:Phenylalanine / Q000032:analysis / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding
D004151:Dipeptides; D004791:Enzyme Inhibitors; D046912:Multiprotein Complexes; C040500:phenylalanylglycine; D010649:Phenylalanine; C029660:glycylphenylalanine; D045304:Cytochromes c; D005998:Glycine