Elucidation of the Aggregation Pathways of Helix-Turn-Helix Peptides: Stabilization at the Turn Region Is Critical for Fibril Formation.
Biochemistry
; 54(26): 4050-62, 2015 Jul 07.
Article
em En
| MEDLINE
| ID: mdl-26070092
ABSTRACT
Aggregation of proteins to fiberlike aggregates often involves a transformation of native monomers to ß-sheet-rich oligomers. This general observation underestimates the importance of α-helical segments in the aggregation cascade. Here, using a combination of experimental techniques and accelerated molecular dynamics simulations, we investigate the aggregation of a 43-residue, apolipoprotein A-I mimetic peptide and its E21Q and D26N mutants. Our study indicates a strong propensity of helical segments not to adopt cross-ß-fibrils. The helix-turn-helix monomeric conformation of the peptides is preserved in the mature fibrils. Furthermore, we reveal opposite effects of mutations on and near the turn region in the self-assembly of these peptides. We show that the E21-R24 salt bridge is a major contributor to helix-turn-helix folding, subsequently leading to abundant fibril formation. On the other hand, the K19-D26 interaction is not required to fold the native helix-turn-helix peptide. However, removal of the charged D26 residue decreases the stability of the helix-turn-helix monomer and consequently reduces the level of aggregation. Finally, we provide a more refined assembly model for the helix-turn-helix peptides from apolipoprotein A-I based on the parallel stacking of helix-turn-helix dimers.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Peptídeos
/
Apolipoproteína A-I
/
Agregados Proteicos
/
Amiloide
Limite:
Humans
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article