title: Conformational switching and fibrillogenesis in the amyloidogenic fragment of apolipoprotein a-I.
abstract: The N-terminal portion of apolipoprotein A-I corresponding to the first 93 residues has been identified as the main component of apolipoprotein A-I fibrils in a form of systemic amyloidosis. We have been able to characterize the process of conformational switching and fibrillogenesis in this fragment of apolipoprotein A-I purified directly from ex vivo amyloid material. The peptide exists in an unstructured form in aqueous solution at neutral pH. The acidification of the solution provokes a collapse into a more compact, intermediate state and the transient appearance of a helical conformation that rapidly converts to a stable, mainly beta-structure in the fibrils. The transition from helical to sheet structure occurs concomitantly with peptide self-aggregation, and fibrils are detected after 72 h. The alpha-helical conformation is induced by the addition of trifluoroethanol and phospholipids. Interaction of the amyloidogenic polypeptide with phospholipids prevents the switching from helical to beta-sheet form and inhibits fibril formation. The secondary structure propensity of the apolipoprotein A-I fragment appears poised between helix and the beta-sheet. These findings reinforce the idea of a delicate balance between natively stabilizing interactions and fatally stabilizing interactions and stress the importance of cellular localization and environment in the maintenance of protein conformation.
authors.affiliation: Department of Biochemistry and Centro Interdipartimentale di Biologia Applicata, University of Pavia, Via Taramelli 3b, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Andreola
authors.forename: Vittorio
authors.initials: V
authors.lastname: Bellotti
authors.forename: Sofia
authors.initials: S
authors.lastname: Giorgetti
authors.forename: Palma
authors.initials: P
authors.lastname: Mangione
authors.forename: Laura
authors.initials: L
authors.lastname: Obici
authors.forename: Monica
authors.initials: M
authors.lastname: Stoppini
authors.forename: Jaume
authors.initials: J
authors.lastname: Torres
authors.forename: Enrico
authors.initials: E
authors.lastname: Monzani
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Merlini
authors.forename: Margaret
authors.initials: M
authors.lastname: Sunde
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry*; D016632:Apolipoprotein A-I / Q000737:chemistry* / Q000378:metabolism; D002942:Circular Dichroism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013050:Spectrometry, Fluorescence; D017550:Spectroscopy, Fourier Transform Infrared; D013997:Time Factors; D014270:Trifluoroethanol / Q000494:pharmacology
chemical_list: D000682:Amyloid; D016632:Apolipoprotein A-I; D010455:Peptides; D010714:Phosphatidylethanolamines; C007510:1,2-dipalmitoyl-3-phosphatidylethanolamine; D014270:Trifluoroethanol