Abstract
Snake venom phospholipases A2 (PLA2s) have sequences and structures very similar to those of mammalian group I and II secretory PLA2s, but they possess many toxic properties, ranging from the inhibition of coagulation to the blockage of nerve transmission, and the induction of muscle necrosis. The biological properties of these proteins are not only due to their enzymatic activity, but also to protein–protein interactions which are still unidentified. Here, we compare sequence alignments of snake venom and mammalian PLA2s, grouped according to their structure and biological activity, looking for differences that can justify their different behavior. This bioinformatics analysis has evidenced three distinct regions, two central and one C-terminal, having amino acid compositions that distinguish the different categories of PLA2s. In these regions, we identified short linear motifs (SLiMs), peptide modules involved in protein–protein interactions, conserved in mammalian and not in snake venom PLA2s, or vice versa. The different content in the SLiMs of snake venom with respect to mammalian PLA2s may result in the formation of protein membrane complexes having a toxic activity, or in the formation of complexes whose activity cannot be blocked due to the lack of switches in the toxic PLA2s, as the motif recognized by the prolyl isomerase Pin1.
Highlights
Phospholipases (PLs) are fundamental lipolytic enzymes for living organisms
The main findings of this analysis are that secretory PLA2s (sPLA2s) can be modified, and in this way probably controlled, by kinases (GSK3, PKA, cyclin-dependent kinase (CDK) and MAPK), and by Pin1, an [ST] phosphorylation-regulated prolyl isomerase, and that some categories of toxic PLA2s lack the short linear motifs (SLiMs) involved in these interactions
The in silico analysis proposed in this study will help in the design of further experimental research, suggesting which amino acid trait may be determinant for the activity of sPLA2s, and with which proteins they can interact
Summary
Phospholipases (PLs) are fundamental lipolytic enzymes for living organisms. They are classified in different families (A1, A2, B, C and D), distinguishable by the position where they induce lipid hydrolysis [1,2]. The PLA2 family is involved in the cleavage of an sn-2 ester bond of the glycerophospholipid substrate, with the consequent generation of 1-acyl-lysophospholipids and free fatty acids, in particular polyunsaturated acids that are metabolized to eicosanoids and bioactive lipid mediators [3,4]. Their key role in inflammation processes and in the arachidonic acid metabolism in mammals is what made such enzymes the most studied PLs. Inside the PLA2 family, it is possible to discriminate different subfamilies based on their structure, localization, and catalytic mechanism [5]. Conventional sPLA2s (groups I, II, V and X) are extracellular small-molecular-weight (13–15 kDa) enzymes, requiring millimolar Ca2+ concentrations for their catalytic activity, principally targeting phospholipids in the extracellular milieu
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