A co-evolutionary approach of serpin and serine proteases using Mirrortree method

Co-evolutionary protein analyses are supported by a variety of methods, many of them applied to verify possible interactions and functional relationships in a taxonomic context. At the molecular level, computational tools are widely used in co-evolutionary studies since its capabilities to process large amounts of data and use diverse approaches, like codon usage or amino acid substitution. Among methods based on amino acid sequences, MirrorTree method is good approach in so far as it evaluates by means of a linear correlation, the distance of two protein families using their phylogenetic trees similarities. Generally speaking, MirrorTree method consists of finding orthologs of the two proteins in multiple species or taxa. This aligns the obtained ortholog sequences, and composes an evolutionary distance matrix from a phylogenetic tree, previously constructed from the multiple sequence alignment, or from the aligned protein pairs. Finally, a Pearson's correlation will determine the co-evolution of protein pairs and predict possible interactions. Serpins are a superfamily of proteins widely distributed among all kingdoms of life, whose members share a common tertiary structure and many of them also exhibit serine proteinase inhibition activities, by virtue of a unique mechanism. On the other hand, serpins are involved in critical biological processes by means of regulation of proteolytic activities, such as apoptosis, inflammation and other signaling pathways in higher mammals. However, the occurrence of serpins and serine proteases is not restricted to higher mammals, since they are also relevant in plants, bacteria, viruses and parasites. Here, we have analyzed a pool of serpin (serine protease inhibitors) sequences and a pool of serine proteases from different taxa, in order to assess the co-evolution of this pair of proteins and its functions. We have applied MirrorTree method on known interacting protease and antiprotease protein pairs, besides sets of putative interacting protein pairs and non-interacting pairs. To our knowledge, is the first time that serine proteases and serpin inhibitors co-evolution in a variety of species is assessed using MirrorTree approaches. Our results suggest that there is a positive co-evolution among these protease-antiprotease pairs, although co-evolution has not followed the same path in all clades analyzed, that is, they have maintained a certain coevolutionary independence.