Amyloid fibrils derived from the apolipoprotein A1 Leu174Ser variant contain elements of ordered helical structure

Palma Mangione, Margaret Sunde, Sofia Giorgetti, Monica Stoppini, Gennaro Esposito, Luca Gianelli, Laura Obici, Lia Asti, Alessia Andreola, Paolo Viglino, Giampaolo Merlini, Vittorio Bellotti

    Research output: Contribution to journalArticle

    Abstract

    We recently described a new apolipoprotein A1 variant presenting a Leu174Ser replacement mutation that is associated with a familial form of systemic amyloidosis displaying predominant heart involvement. We have now identified a second unrelated patient with very similar clinical presentation and carrying the identical apolipoprotein A1 mutation. In this new patient the main protein constituent of the amyloid fibrils is the polypeptide derived from the first 93 residues of the protein, the identical fragment to that found in the patient previously described to carry this mutation. The X-ray fiber diffraction pattern obtained from preparations of partially aligned fibrils displays the cross-β reflections characteristic of all amyloid fibrils. In addition to these cross-β reflections, other reflections suggest the presence of well-defined coiled-coil helical structure arranged with a defined orientation within the fibrils. In both cases the fibrils contain a trace amount of full-length apolipoprotein A1 with an apparent prevalence of the wild-type species over the variant protein. We have found a ratio of full-length wild-type to mutant protein in plasma HDL of three to one. The polypeptide 1-93 purified from natural fibrils can be solubilized in aqueous solutions containing denaturants, and after removal of denaturants it acquires a monomeric state that, based on CD and NMR studies, has a predominantly random coil structure. The addition of phospholipids to the monomeric form induces the formation of some helical structure, thought most likely to occur at the C-terminal end of the polypeptide.

    Original languageEnglish (US)
    Pages (from-to)187-199
    Number of pages13
    JournalProtein Science
    Volume10
    Issue number1
    DOIs
    StatePublished - Mar 28 2001

    Fingerprint

    Apolipoprotein A-I
    Amyloid
    Peptides
    Mutation
    Proteins
    Amyloidosis
    Mutant Proteins
    X-Ray Diffraction
    Diffraction patterns
    Phospholipids
    Nuclear magnetic resonance
    Plasmas
    X rays
    Fibers

    Keywords

    • Amyloidosis
    • Apolipoprotein A1
    • Fibrillogenesis
    • Proteolysis

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Biology

    Cite this

    Mangione, P., Sunde, M., Giorgetti, S., Stoppini, M., Esposito, G., Gianelli, L., ... Bellotti, V. (2001). Amyloid fibrils derived from the apolipoprotein A1 Leu174Ser variant contain elements of ordered helical structure. Protein Science, 10(1), 187-199. https://doi.org/10.1110/ps.29201

    Amyloid fibrils derived from the apolipoprotein A1 Leu174Ser variant contain elements of ordered helical structure. / Mangione, Palma; Sunde, Margaret; Giorgetti, Sofia; Stoppini, Monica; Esposito, Gennaro; Gianelli, Luca; Obici, Laura; Asti, Lia; Andreola, Alessia; Viglino, Paolo; Merlini, Giampaolo; Bellotti, Vittorio.

    In: Protein Science, Vol. 10, No. 1, 28.03.2001, p. 187-199.

    Research output: Contribution to journalArticle

    Mangione, P, Sunde, M, Giorgetti, S, Stoppini, M, Esposito, G, Gianelli, L, Obici, L, Asti, L, Andreola, A, Viglino, P, Merlini, G & Bellotti, V 2001, 'Amyloid fibrils derived from the apolipoprotein A1 Leu174Ser variant contain elements of ordered helical structure', Protein Science, vol. 10, no. 1, pp. 187-199. https://doi.org/10.1110/ps.29201
    Mangione, Palma ; Sunde, Margaret ; Giorgetti, Sofia ; Stoppini, Monica ; Esposito, Gennaro ; Gianelli, Luca ; Obici, Laura ; Asti, Lia ; Andreola, Alessia ; Viglino, Paolo ; Merlini, Giampaolo ; Bellotti, Vittorio. / Amyloid fibrils derived from the apolipoprotein A1 Leu174Ser variant contain elements of ordered helical structure. In: Protein Science. 2001 ; Vol. 10, No. 1. pp. 187-199.
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    AU - Stoppini, Monica

    AU - Esposito, Gennaro

    AU - Gianelli, Luca

    AU - Obici, Laura

    AU - Asti, Lia

    AU - Andreola, Alessia

    AU - Viglino, Paolo

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