title: Protein conformational perturbations in hereditary amyloidosis: Differential impact of single point mutations in ApoAI amyloidogenic variants.
abstract: Amyloidoses are devastating diseases characterized by accumulation of misfolded proteins which aggregate in fibrils. Specific gene mutations in Apolipoprotein A I (ApoAI) are associated with systemic amyloidoses. Little is known on the effect of mutations on ApoAI structure and amyloid properties. Here we performed a physico-chemical characterization of L75P- and L174S-amyloidogenic ApoAI (AApoAI) variants to shed light on the effects of two single point mutations on protein stability, proteolytic susceptibility and aggregation propensity. Both variants are destabilized in their N-terminal region and generate fibrils with different morphological features. L75P-AApoAI is significantly altered in its conformation and compactness, whereas a more flexible and pronounced aggregation-competent state is associated to L174S-AApoAI. These observations point out how single point mutations in ApoAI gene evocate differences in the physico-chemical and conformational behavior of the corresponding protein variants, with the common feature of diverting ApoAI from its natural role towards a pathogenic pathway.
authors.affiliation: Department of Chemical Sciences, University of Naples Federico II, 80126 Naples, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Del Giudice
authors.affiliation: Department of Chemical Sciences, University of Naples Federico II, 80126 Naples, Italy; Istituto Nazionale di Biostrutture e Biosistemi (INBB), Rome, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Arciello
authors.affiliation: Department of Chemical Sciences, University of Naples Federico II, 80126 Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Itri
authors.affiliation: Department of Chemical Sciences, University of Naples Federico II, 80126 Naples, Italy; Institute of Biostructures and Bioimaging-CNR, Via Mezzocannone 16, 80134 Naples, Italy.
authors.forename: Antonello
authors.initials: A
authors.lastname: Merlino
authors.affiliation: Department of Chemical Sciences, University of Naples Federico II, 80126 Naples, Italy; Istituto Nazionale di Biostrutture e Biosistemi (INBB), Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Monti
authors.affiliation: Institute of Biostructures and Bioimaging-CNR, Via Mezzocannone 16, 80134 Naples, Italy; Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università di Napoli, Caserta, Italy.
authors.forename: Martina
authors.initials: M
authors.lastname: Buonanno
authors.affiliation: Department of Physics, University of Genoa, Genoa, Italy.
authors.forename: Amanda
authors.initials: A
authors.lastname: Penco
authors.affiliation: Department of Chemical Sciences, University of Naples Federico II, 80126 Naples, Italy; Istituto Nazionale di Biostrutture e Biosistemi (INBB), Rome, Italy.
authors.forename: Diana
authors.initials: D
authors.lastname: Canetti
authors.affiliation: Department of Chemical Sciences, University of Naples Federico II, 80126 Naples, Italy.
authors.forename: Ganna
authors.initials: G
authors.lastname: Petruk
authors.affiliation: Institute of Biostructures and Bioimaging-CNR, Via Mezzocannone 16, 80134 Naples, Italy.
authors.forename: Simona Maria
authors.initials: SM
authors.lastname: Monti
authors.affiliation: Department of Physics, University of Genoa, Genoa, Italy; Istituto Nazionale di Biostrutture e Biosistemi (INBB), Rome, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Relini
authors.affiliation: Department of Chemical Sciences, University of Naples Federico II, 80126 Naples, Italy; Istituto Nazionale di Biostrutture e Biosistemi (INBB), Rome, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Pucci
authors.affiliation: Department of Chemical Sciences, University of Naples Federico II, 80126 Naples, Italy; Istituto Nazionale di Biostrutture e Biosistemi (INBB), Rome, Italy.
authors.forename: Renata
authors.initials: R
authors.lastname: Piccoli
authors.affiliation: Department of Chemical Sciences, University of Naples Federico II, 80126 Naples, Italy; Istituto Nazionale di Biostrutture e Biosistemi (INBB), Rome, Italy. Electronic address: mdmonti@unina.it.
authors.forename: Daria Maria
authors.initials: DM
authors.lastname: Monti
mesh_terms: D028226:Amyloidosis, Familial / Q000235:genetics*; D016632:Apolipoprotein A-I / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D056004:Molecular Dynamics Simulation; D017354:Point Mutation; D066329:Protein Aggregates; D011487:Protein Conformation; D017433:Protein Structure, Secondary
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D066329:Protein Aggregates
keywords: Amyloidosis; Apolipoprotein A I; Conformational diseases; Protein stability