title: Elucidation of the Aggregation Pathways of Helix-Turn-Helix Peptides: Stabilization at the Turn Region Is Critical for Fibril Formation.
abstract: Aggregation of proteins to fiberlike aggregates often involves a transformation of native monomers to β-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-β-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.
authors.forename: Thanh D
authors.initials: TD
authors.lastname: Do
authors.forename: Ali
authors.initials: A
authors.lastname: Chamas
authors.forename: Xueyun
authors.initials: X
authors.lastname: Zheng
authors.affiliation: §Department of Chemistry, Westmont College, Santa Barbara, California 93108, United States.
authors.forename: Aaron
authors.initials: A
authors.lastname: Barnes
authors.affiliation: §Department of Chemistry, Westmont College, Santa Barbara, California 93108, United States.
authors.forename: Dayna
authors.initials: D
authors.lastname: Chang
authors.affiliation: §Department of Chemistry, Westmont College, Santa Barbara, California 93108, United States.
authors.forename: Tjitske
authors.initials: T
authors.lastname: Veldstra
authors.affiliation: §Department of Chemistry, Westmont College, Santa Barbara, California 93108, United States.
authors.forename: Harmeet
authors.initials: H
authors.lastname: Takhar
authors.affiliation: §Department of Chemistry, Westmont College, Santa Barbara, California 93108, United States.
authors.forename: Nicolette
authors.initials: N
authors.lastname: Dressler
authors.affiliation: §Department of Chemistry, Westmont College, Santa Barbara, California 93108, United States.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Trapp
authors.affiliation: §Department of Chemistry, Westmont College, Santa Barbara, California 93108, United States.
authors.forename: Kylie
authors.initials: K
authors.lastname: Miller
authors.affiliation: §Department of Chemistry, Westmont College, Santa Barbara, California 93108, United States.
authors.forename: Audrene
authors.initials: A
authors.lastname: McMahon
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Meredith
authors.forename: Joan-Emma
authors.initials: JE
authors.lastname: Shea
authors.affiliation: §Department of Chemistry, Westmont College, Santa Barbara, California 93108, United States.
authors.forename: Kristi
authors.initials: K
authors.lastname: Lazar Cantrell
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bowers
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D016632:Apolipoprotein A-I / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D017354:Point Mutation; D066329:Protein Aggregates; D017433:Protein Structure, Secondary
chemical_list: D000682:Amyloid; D016632:Apolipoprotein A-I; D010455:Peptides; D066329:Protein Aggregates