Short Linear Motifs Characterizing Snake Venom and Mammalian Phospholipases A2

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.

Catalytically Active Snake Venom PLA2 Enzymes: An Overview of Its Elusive Mechanisms of Reaction

“…Over 200 nonredundant, complete, and reviewed sequences of svPLA 2 s can be found in the UniProtKB Database (accessed in March) . Their primary structure shows a significant percentage of sequence identity among species, and the X-ray structures deposited in the Protein Data Bank (PDB) (e.g., snake venoms, humans, and bovines) revealed that svPLA 2 groups have a markedly similar architecture. ,,, A sequence alignment denoting the conservation of the catalytic center of different species of secreted PLA 2 is shown in Figure , and a sequence identity matrix is presented in Supporting Information (SI), Table S1.…”

“…This loop is followed by the second α-helix (α2), which binds to antiparallel β-sheets cross-linked by disulfide bonds (β-wing region). Following this region is the α-helix 3 (α3), which binds to an exceptionally flexible region, the C-terminal loop, that is believed to be involved in the biological effects of these toxins , and allows it to change its conformation and interact with natural lipids. , The crystal structures of svPLA 2 -GIA from the Chinese cobra ( Naja atra ) and svPLA 2 -GIIA from the Indian saw-scaled viper ( Echis carinatus ) venom were used to illustrate these structural characteristics (Figure ). In addition, structures of bovine pancreatic and human synovial PLA 2 are also shown (SI, Figure S1) to emphasize the above-mentioned similar architecture.…”

“…Based on structural and functional features, the PLA 2 superfamily is divided into four principal categories: the Ca 2+ -dependent secreted, further subdivided into 17 groups, the Ca 2+ -dependent cytosolic, the Ca 2+ -independent, and the lipoprotein-associated (LpPLA 2 s) phospholipase A 2 enzymes. , All svPLA 2 are of the secreted category. The details concerning the remaining types and groups fall out of the scope of this Perspective and can be found in several excellent works on this matter. , …”

“…The svPLA 2 are small extracellular proteins with a molecular weight of 14–18 kDa, 120–135 amino acid residues, and 6–8 disulfide bridges that contribute to their high degree of stability and a pH optimum at 7. , In addition, these enzymes are characterized by a His48/Asp99 dyad at the active site with a Ca 2+ -binding loop and the requirement of mM Ca 2+ for catalytic activity. ,, Besides snake venom, secreted PLA 2 are found in scorpion and bee venom, among other animal venoms, and in several body fluids as nontoxic enzymes, including blood plasma, pancreatic secretions, seminal fluid, or tears. , svPLA 2 from elapid and viperid snakes share six disulfide bonds and an additional one in a different location on each …”

Secretory Phospholipases A2, from Snakebite Envenoming to a Myriad of Inflammation Associated Human Diseases—What Is the Secret of Their Activity?

“…By comparing the sequence of sPLA2s from snake venom with the corresponding human homologues, differences emerged in the short linear motifs (SLiMs) conserved in the two protein categories. This comparison showed that human proteins differ from animal venom in the presence of SLiMs susceptible to undergoing PTMs by the S/T kinases CDK, GSK3, PKA, MAPK, by tyrosine kinases, and by Pin1, a [ST] phosphorylation-regulated prolyl isomerase [ 62 ]. These differences in the sites subjected to PTMs may give the toxins the possibility of establishing different molecular interactions than mammalian sPLA2s and/or confer different resistance to degradative processes via the ubiquitin-proteasome pathway or micro autophagy.…”