Structural properties of apolipoprotein A1 associated with evolutionary constraints

MASSON T; GISONNO, ROMINA A.; TRICERRI ALEJANDRA; NAHUEL ALBERTO RAMELLA

San Luis

Congreso; XLVIII Reunión Anual Sociedad Argentina de Biofísica.; 2019

Sociedad Argentina de Biofísica

Apolipoprotein A-I (APOA1) is the main protein of plasma high-density lipoproteins. It is involved in removing excess of cell cholesterol and protect against atherosclerosis. Extensive research supports that the cardio protection attributed to the protein is due to its active role in the reverse cholesterol transport pathway and in the protection against endothelial dysfunction. Several apoA-I mutants have been identified as pathological in familial systemic amyloidosis, with different tissue-specific deposition. Most of the mutations described in patients occur within two ?hot spots? in the protein sequence: the N-terminus (residues 26-100) and a short C-terminal sequence (residues 173-178). This tendency highlights the deep coupling between protein sequence and phenotype exhibited by the different mutants. At the interface of biophysics and molecular evolution there is a set of fundamental processes that shape the molecular function of proteins. Different sites and sectors within a protein sequence evolve at different rates; this evolutionary rate heterogeneity across protein site is useful to study the interplay of functional and structural constraints. Moreover, co-evolution between residues in a protein is a fundamental component for understanding the complex evolutionary design of proteins.In this work we aimed to deepen our understanding of APOA1 structural design throughout the interrogation of its molecular evolution processes in vertebrate organisms. Our approach involved the phylogenetic reconstruction of APOA1 evolutionary history and the estimation of the amino acid substitution rates across the protein sequence. We also employed multiple sequence alignments (MSA) to calculate residues co-evolution patterns using Direct Coupling Analysis (DCA) and GREMLIN (Generative REgularized ModeLs of proteINs). Our data suggest novel functionally relevant residues and co-evolving pairs inside APOA1 structure, which could help understanding the molecular principles protein aggregation in pathological amyloidosis.AcknowledgementsAuthors acknowledge fundings of ANPCyT (PICT 2016-0849) and UNLP (M187)