title: Effects of the known pathogenic mutations on the aggregation pathway of the amyloidogenic peptide of apolipoprotein A-I.
abstract: The 93-residue N-terminal fragment of apolipoprotein A-I (ApoA-I) is the major constituent of fibrils isolated from patients affected by the amyloidosis caused by ApoA-I mutations. We have prepared eight polypeptides corresponding to all the currently known amyloidogenic variants of the N-terminal region of ApoA-I, other than a truncation mutation, and investigated their aggregation kinetics and the associated structural modifications. All the variants adopted a monomeric highly disordered structure in solution at neutral pH, whereas acidification of the solution induced an unstable α-helical conformation and the subsequent aggregation into the cross-β structure aggregate. Two mutations (Δ70-72 and L90P) almost abrogated the lag phase of the aggregation process, three mutations (Δ60-71, L75P, and W50R) significantly accelerated the aggregation rate by 2- to 3-fold, while the remaining three variants (L64P, L60R, and G26R) were not significantly different from the wild type. Therefore, an increase in aggregation propensity cannot explain per se the mechanism of the disease for all the variants. Prediction of the protection factors for hydrogen exchange in the native state of full-length protein reveals, in almost all the variants, an expansion of the conformational fluctuations that could favour the proteolytic cleavage and the release of the amyloidogenic peptide. Such an event seems to be a necessary prerequisite for ApoA-I fibrillogenesis in vivo, but the observed increased aggregation propensity of certain variants can have a strong influence on the severity of the disease, such as an earlier onset and a faster progression.
authors.affiliation: Department of Biochemistry, University of Pavia, 27100 Pavia, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Raimondi
authors.forename: Fulvio
authors.initials: F
authors.lastname: Guglielmi
authors.forename: Sofia
authors.initials: S
authors.lastname: Giorgetti
authors.forename: Sonia
authors.initials: S
authors.lastname: Di Gaetano
authors.forename: Angela
authors.initials: A
authors.lastname: Arciello
authors.forename: Daria M
authors.initials: DM
authors.lastname: Monti
authors.forename: Annalisa
authors.initials: A
authors.lastname: Relini
authors.forename: Daniela
authors.initials: D
authors.lastname: Nichino
authors.forename: Silvia M
authors.initials: SM
authors.lastname: Doglia
authors.forename: Antonino
authors.initials: A
authors.lastname: Natalello
authors.forename: Piero
authors.initials: P
authors.lastname: Pucci
authors.forename: Palma
authors.initials: P
authors.lastname: Mangione
authors.forename: Laura
authors.initials: L
authors.lastname: Obici
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Merlini
authors.forename: Monica
authors.initials: M
authors.lastname: Stoppini
authors.forename: Paul
authors.initials: P
authors.lastname: Robustelli
authors.forename: Gian Gaetano
authors.initials: GG
authors.lastname: Tartaglia
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.forename: Renata
authors.initials: R
authors.lastname: Piccoli
authors.forename: Vittorio
authors.initials: V
authors.lastname: Bellotti
mesh_terms: D000682:Amyloid / Q000235:genetics / Q000378:metabolism*; D016632:Apolipoprotein A-I / Q000235:genetics* / Q000378:metabolism*; D002942:Circular Dichroism; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000682:Amyloid; D016632:Apolipoprotein A-I; D010455:Peptides