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

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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