Conformational switching and fibrillogenesis in the amyloidogenic fragment of apolipoprotein A-I

Alessia Andreola, Vittorio Bellotti, Sofia Giorgetti, Palma Mangione, Laura Obici, Monica Stoppini, Jaume Torres, Enrico Monzani, Giampaolo Merlini, Margaret Sunde

Research output: Contribution to journalArticle

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 β-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 α-helical conformation is induced by the addition of trifluoroethanol and phospholipids. Interaction of the amyloidogenic polypeptide with phospholipids prevents the switching from helical to β-sheet form and inhibits fibril formation. The secondary structure propensity of the apolipoprotein A-I fragment appears poised between helix and the β-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.

Original languageEnglish
Pages (from-to)2444-2451
Number of pages8
JournalJournal of Biological Chemistry
Volume278
Issue number4
DOIs
Publication statusPublished - Jan 24 2003

ASJC Scopus subject areas

  • Biochemistry

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    Andreola, A., Bellotti, V., Giorgetti, S., Mangione, P., Obici, L., Stoppini, M., Torres, J., Monzani, E., Merlini, G., & Sunde, M. (2003). Conformational switching and fibrillogenesis in the amyloidogenic fragment of apolipoprotein A-I. Journal of Biological Chemistry, 278(4), 2444-2451. https://doi.org/10.1074/jbc.M204801200