title: Human apolipoprotein A-I natural variants: molecular mechanisms underlying amyloidogenic propensity.
abstract: Human apolipoprotein A-I (apoA-I)-derived amyloidosis can present with either wild-type (Wt) protein deposits in atherosclerotic plaques or as a hereditary form in which apoA-I variants deposit causing multiple organ failure. More than 15 single amino acid replacement amyloidogenic apoA-I variants have been described, but the molecular mechanisms involved in amyloid-associated pathology remain largely unknown. Here, we have investigated by fluorescence and biochemical approaches the stabilities and propensities to aggregate of two disease-associated apoA-I variants, apoA-IGly26Arg, associated with polyneuropathy and kidney dysfunction, and apoA-ILys107-0, implicated in amyloidosis in severe atherosclerosis. Results showed that both variants share common structural properties including decreased stability compared to Wt apoA-I and a more flexible structure that gives rise to formation of partially folded states. Interestingly, however, distinct features appear to determine their pathogenic mechanisms. ApoA-ILys107-0 has an increased propensity to aggregate at physiological pH and in a pro-inflammatory microenvironment than Wt apoA-I, whereas apoA-IGly26Arg elicited macrophage activation, thus stimulating local chronic inflammation. Our results strongly suggest that some natural mutations in apoA-I variants elicit protein tendency to aggregate, but in addition the specific interaction of different variants with macrophages may contribute to cellular stress and toxicity in hereditary amyloidosis.
authors.affiliation: Instituto de Investigaciones Bioquímicas de La Plata, CONICET, La Plata, Buenos Aires, Argentina.
authors.forename: Nahuel A
authors.initials: NA
authors.lastname: Ramella
authors.forename: Guillermo R
authors.initials: GR
authors.lastname: Schinella
authors.forename: Sergio T
authors.initials: ST
authors.lastname: Ferreira
authors.forename: Eduardo D
authors.initials: ED
authors.lastname: Prieto
authors.forename: María E
authors.initials: ME
authors.lastname: Vela
authors.forename: José Luis
authors.initials: JL
authors.lastname: Ríos
authors.forename: M Alejandra
authors.initials: MA
authors.lastname: Tricerri
authors.forename: Omar J
authors.initials: OJ
authors.lastname: Rimoldi
mesh_terms: D019943:Amino Acid Substitution; D058227:Amyloidogenic Proteins / Q000737:chemistry* / Q000235:genetics*; D000818:Animals; D016632:Apolipoprotein A-I / Q000737:chemistry* / Q000235:genetics*; D002460:Cell Line; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D050505:Mutant Proteins / Q000737:chemistry* / Q000235:genetics*; D017510:Protein Folding; D055503:Protein Multimerization; D055550:Protein Stability; D017433:Protein Structure, Secondary
chemical_list: D058227:Amyloidogenic Proteins; D016632:Apolipoprotein A-I; D050505:Mutant Proteins