Role of extracellular matrix components in apolipoprotein A-I amyloidosis: Differential interactions and organ-specificity

CALABRESE, GRACIELA C.; NAHUEL A. RAMELLA; ROSU, S. A; M. ALEJANDRA TRICERRI

Buenos Aires

Encuentro; XLIX Reunion anual SAB; 2021

Sociedad Argentina de Biofísica

Protein misfolding is involved in chronic diseases known as amyloidosis. Among other, human apolipoprotein A-I (apoA-I) natural mutants are retained specifically in different tissues, inducing protein aggregates that cause organ damage. The reason of such selectivity is far to be known. The variant Arg173Pro, is associated with cardiac amyloidosis. With the hypothesis that the extracellular matrix (ECM) plays a role in the retention of this variant, we have previously shown that Arg173Pro (but not the Wt) interacts with heparin (HEP), a model of glycosaminoglycans (GAGs) present in proteoglycans. We here expand those results and used different approaches (electrophoresis, fluorescence chromatography), to test and characterize the interaction with more biological GAGs such as dermatan sulphate (DS). Our results indicate that this variant binds with higher affinity than the Wt to both GAGs (HEP and DS). Elution profiles through a column with HEP covalently linked indicated that the binding to DS displaces the interaction with HEP at physiological pH. The protein-GAGs complexes are detected by the fluorescent dye toluidine blue and are characterized by native electrophoresis. The GAG: protein complexes were resolved by polyacrylamide gel electrophoresis, and developed by silver nitrate staining. The Arg173Pro variant is mostly retained by interacting with DS and HEP.This finding is interesting, since both GAGs are associated with amyloid deposits The results obtained here partially support the particular tropism that this variant may have for the tissues it affects, since GAGs such as HEP and heparan sulfate are concentrated in myocardium. In addition, the study of the protein-GAGs interaction is clue for the synthesis of sulphated compounds, which could act as inhibitors of this interaction. Previous laboratory results confirm in synthetic models that apoA-I Arg173Pro interacts more with matrices with a higher sulphated content.We conclude that a delicate specificity may determine the interaction of apoA-I variants with the components of the ECM. Particularly, with the charge provided by dermatan sulphate and heparan sulphate, these results suggest that the retention of Arg173Pro could be mediated by this interaction.