CONICET | Buscador de Institutos y Recursos Humanos

Glycosaminoglycans (GAGs) are ubiquitous components ofthe cell surface and extracellular matrix (ECM) of all multicellular animals. They specifically regulate biological processes through interactions with a large repertoire of proteins. Owing to these interactions and diverse effects observed during in vitro, ex vivo and in vivo experiments, manifold biological/pharmacological activities have been attributed to them. On the other hand, protein interaction with GAGs has been demonstrated as a factor that may favor protein aggregation or misfolding identified in lesions of patients suffering from amyloidosis. We previously showed that apolipoprotein A-I (apoA-I) Arg173Pro (a natural mutant involved in cardiac amyloidosis) but not the wild type protein (Wt) bound heparin at pH 7.4 1, 2. This indicates that selective interactions of this variant may occur with GAGs. In this work, we got deep insight into this interaction, by taking advantage of chromatographic approaches. The relative higher interaction of Arg173Pro respect to Wt with heparin was proved by the longer elution time of the protein by affinity chromatography through a support with heparin covalently bound to the matrix.By modifying the ionic strength, it can be proposed that electrostatic interactions take place. Following, Arg173Pro was incubated with the GAG at a 1:3 molar ratiorespectively, and the product resolved by size exclusion FPLC. The shift in the migration of the protein when is eluted in the presence of heparin indicates that heparin partially disarranges the physiological dimer of the apoA-I variant. Our results strongly support that at least in part the interaction of apoA-I variants with components of the ECM might alter the delicate protein folding and may participate in the cellular trophism of the variants in the amyloidosis disease. References: Rosú et al. PLoS ONE 10(5): e0124946. doi:10.1371/ journal.pone.0124946. 2. Rosú et al Protein J. 2017 Aug;36(4):374-383,