Evolutionary histories of expanded peptidase families in Schistosoma mansoni

Abstract

Schistosoma mansoni is one of the three main causative agents of human schistosomiasis, a major health problem with a vast socio-economic impact. Recent advances in the proteomic analysis of schistosomes have revealed that peptidases are the main virulence factors involved in the pathogenesis of this disease. In this context, evolutionary studies can be applied to identify peptidase families that have been expanded in genomes over time in response to different selection pressures. Using a phylogenomic approach, we searched for expanded endopeptidase families in the S. mansoni predicted proteome with the aim of contributing to the knowledge of such enzymes as potential therapeutic targets. We found three endopeptidase families that comprise leishmanolysins (metallopeptidase M8 family), cercarial elastases (serine peptidase S1 family) and cathepsin D proteins (aspartic peptidase A1 family). Our results suggest that the Schistosoma members of these families originated from successive gene duplication events in the parasite lineage after its diversification from other metazoans. Overall, critical residues are conserved among the duplicated genes/proteins. Furthermore, each protein family displays a distinct evolutionary history. Altogether, this work provides an evolutionary view of three S. mansoni peptidase families, which allows for a deeper understanding of the genomic complexity and lineage-specific adaptations potentially related to the parasitic lifestyle.Key words: phylogenomics -maximum likelihood analysis -homology predictionfunctional annotation -proteases -paralogous families -parasite genomics S. mansoni peptidase families • Larissa Lopes Silva et al. 865et al. 2010). In general, cysteine peptidases have cysteine and histidine residues forming their "catalytic dyad". Meanwhile, other active site residues have been found. Glutamic peptidases have glutamic acid residues as their primary catalytic residues, which are probably the nucleophilic attack mediators involved in the catalysis (Fujinaga et al. 2004, Rawlings et al. 2010. In metallopeptidases, the catalytic mechanism usually involves a single catalytic zinc ion tetrahedrally coordinated by one glutamate and two histidine residues (Rawlings et al. 2010). Serine peptidases have serine residues at their active sites, which together with two other variable amino acids constitute the "catalytic triad" (Hedstrom 2002, Rawlings et al. 2010. Threonine peptidases have threonine residues as their nucleophiles during catalysis. For unknown peptidases, the active site residues have not yet been determined. Evolutionary analyses have been applied to a broad range of studies, which include the identification of gene/protein families that have expanded in a specific lineage over evolutionary time and possibly indicate the existence of selective pressure (Irving et al. 2003, Sargeant et al. 2006, Nahum & Pereira 2008, Robinson et al. 2008, Wu et al. 2009, Huzurbazar et al. 2010. The availability of faster and more powerful computers combined with the development of...

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“…The search for new drug targets based on evolutionary analyses using S. mansoni genomic/proteomic data has been performed (Silva et al, 2011, 2012). Such studies have improved the S. mansoni functional annotation, allowed for a deeper understanding of the genomic complexity and lineage-specific adaptations potentially related to the parasitic lifestyle, and pointed out several proteins as potential drug targets, including proteases.…”

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“…Among the most significant protein expansions in S. mansoni we identified tetraspanins, fucosyltransferases, venom allergen-like proteins (SmVAL), tegumental-allergen-like proteins (SmTAL), leishmanolysins, and elastases, which were previously proposed as drug targets, once they can be related to morphological or physiological specificities of this parasite [5,20,61-65]. In these cases, the protein family membership ranged from 6 to 23 paralogs encoded in the parasite’s genome.…”

“…Recent studies have also revealed that these proteases can be employed by schistosomes to overcome or evade the host immune response [77,78]. Members of S. mansoni peptidase families such as leishmanolysins, cercarial elastases, and cathepsin D proteins were subjected to a detailed study in respect to their domain architectures, functional properties, and evolutionary relationships as described elsewhere [65]. …”

New Frontiers inSchistosomaGenomics and Transcriptomics

“…Moreover, phylogenomics has unraveled the distinct evolutionary histories of three expanded endopeptidase families in S. mansoni [45]. This analysis included members of the metallopeptidase M8, serine peptidase S1, and aspartic peptidase A1 families, which were originated from successive events of gene duplication followed by divergence in the parasite lineage after its diversification from other metazoans.…”

“…Leishmanolysins, which are members of the metallopeptidase M8 family, were analysed in detail corroborating the potential of these enzymes as future therapeutic targets [45]. …”