In-silico analysis of caspase-3 and -7 proteases from blood-parasitic Schistosoma species (Trematoda) and their human host

Abstract

Proteolytic enzymes of the caspase family, which reside as latent precursors in most nucleated metazoan cells, are core effectors of apoptosis. Of them, the executioner caspases-3 and-7 exist within the cytosol as inactive dimers and are activated by a process called dimerization. Caspase inhibition is looked upon as a promising approach for treating multiple diseases. Though caspases have been extensively studied in the human system, their role in eukaryotic pathogens and parasites of human hosts has not drawn enough attention. In protein sequence analysis, caspases of blood flukes (Schistosoma spp) were revealed to have a low sequence identity with their counterparts in human and other mammalian hosts, which encouraged us to analyse interacting domains that participate in dimerization of caspases in the parasite and to reveal differences, if any, between the host-parasite systems. Significant differences in the molecular surface arrangement of the dimer interfaces reveal that in schistosomal caspases only eight out of forty dimer conformations are similar to human caspase structures. Thus, the parasite-specific dimer conformations (that are different from caspases of the host) may emerge as potential drug targets of therapeutic value against schistosomal infections. Three important factors namely, the size of amino acids, secondary structures and geometrical arrangement of interacting domains influence the pattern of caspase dimer formation, which, in turn, is manifested in varied structural conformations of caspases in the parasite and its human hosts. Background: Schistosomiasis is a parasitic disease that is caused by blood flukes (trematodes) and leads to chronic ill health. According to the World Health Organization (WHO), it affects at least 240 million people worldwide and more than 700 million people are at risk in endemic areas. The infection is prevalent in tropical and subtropical areas among poor communities having no access to potable water and adequate sanitation. Transmission of infection occurs through snails (infesting water bodies), which release the infective free swimming larval stage-the cercaria; the latter enters the mammalian host directly penetrating via a cutaneous route. The causative organisms of