Amyloidogenic propensity of a natural variant of human apolipoprotein A-I: stability and interaction with ligands.

ROSU, S. A.; RIMOLDI. O. J.; PRIETO, E. D.; CURTO, L. M.; DELFINO, J. M.; RAMELLA, N.; TRICERRI, M. A.

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2015

1932-6203

A number of naturally occurring mutations of human apolipoprotein A-I (apoA-I) have beenassociated with hereditary amyloidoses. The molecular mechanisms involved in amyloidassociatedpathology remain largely unknown. Here we examined the effects of the Arg173-Pro point mutation in apoA-I on the structure, stability, and aggregation propensity, as wellas on the ability to bind to putative ligands. Our results indicate that the mutation induces adrastic loss of stability, and a lower efficiency to bind to phospholipid vesicles at physiologicalpH, which could determine the observed higher tendency to aggregate as pro-amyloidogeniccomplexes. Incubation under acidic conditions does not seem to induce significantdesestabilization or aggregation tendency, neither does it contribute to the binding of themutant to sodium dodecyl sulfate. While the binding to this detergent is higher for the mutantas compared to wt apoA-I, the interaction of the Arg173Pro variant with heparin depends onpH, being lower at pH 5.0 and higher than wt under physiological pH conditions. We suggestthat binding to ligands as heparin or other glycosaminoglycans could be key events tuningthe fine details of the interaction of apoA-I variants with the micro-environment, and probablyeliciting the toxicity of these variants in hereditary amyloidoses.