Molecular mechanisms that determine the pathogenicity of human Apolipoprotein A-I natural amyloidogenic Variants.

ROSU, SILVANA; NAHUEL A. RAMELLA; GADDI, GISELLA; GABRIELA S. FINARELLI; EDUARDO D. PRIETO,; GUILLERMO R. SCHINELLA; M. ALEJANDRA TRICERRI

San Carlos de Bariloche

Congreso; III Latin American Federation of Biophysical Societies (LAFeBS). IX IberoAmerican Congress of Biophysics . XLV Reunion Anual SAB; 2016

Sociedad Argentina de Biofisica

Protein aggregation is characterized by a remarkable polymorphism anddifferent conformations have been identified as toxic intermediates insome neurodegenerative diseases1. Amyloidosis induced by naturalmutants of apolipoprotein A-I (apoA-I) depends on the protein variantand affects different organs such as heart, liver and kidney amongothers. In previous studies we have demonstrated that different apoA-Imutants show increased tendency to aggregate giving rise to differentconformations depending on the incubation conditions 2,3. Here weconstructed four natural amyloidogenic variants (Arg173Pro, Gly26-Arg, Leu60Arg and Lys107-0), and compared their behavior with theprotein with the wild type sequence (Wt). All the mutants are less stableand with a more flexible structure than Wt at pH 7,4, which could inpart explain their aggregation tendency. While Wt does not bind heparin(as a model of Glycosamine Glycane) at this pH, Arg173Pro formsprotein-heparin complexes and binds negative lipids with higher effi-ciency. Mild acidic pH induces a loss of the native structure, whichwas characterized by Atomic Force Microscopy as oligomer-like conformations.Interestingly, Gly26Arg and Arg173Pro (but not Lys107-0), elicit pro-inflammatory responses from macrophages such as Interleukin 1- beta (IL1) release, and the presence of a pro-oxidant milieu favors the yield of fiber-like species. We strongly suggest that common and specific mechanisms of amyloid cascades determine apoA-I variants? pathogenesis and that a chronic pro-inflammatory environment is either cause or consequence of protein misfolding. The knowledge of the specific pathological pathways is clue in order to apply strategies to avoid organ damage