4q6x
Structure of phospholipase D Beta1B1i from Sicarius terrosus venom at 2.14 A resolution
Structural highlights
FunctionBIB11_SICTE Dermonecrotic toxins cleave the phosphodiester linkage between the phosphate and headgroup of certain phospholipids (sphingolipid and lysolipid substrates), forming an alcohol (often choline) and a cyclic phosphate (PubMed:25752604). This toxin acts on lysophosphatidylethanolamine (LPE) and ceramide phosphoethanolamine (CPE) with high activity (PubMed:25752604). This toxin acts on sphingomyelin (SM) with very low activity and is not active on lysophosphatidylserine (LPS), lysophosphatidylcholine (LPC) and lysophosphatidylglycerol (LPG) (PubMed:25752604). It acts by transphosphatidylation, releasing exclusively cyclic phosphate as second products (PubMed:25752604). It is not surprising that spider toxins have affinity for ethanolamine-containing sphingolipids since they are common in insect prey (PubMed:25752604). Induces dermonecrosis, hemolysis, increased vascular permeability, edema, inflammatory response, and platelet aggregation (By similarity).[UniProtKB:P0CE80][1] Publication Abstract from PubMedVenoms of the sicariid spiders contain phospholipase D enzyme toxins that cause severe dermonecrosis and even death in humans. These enzymes convert sphingolipid and lysolipid substrates to cyclic phosphates by activating a hydroxyl nucleophile present in both classes of lipid. The most medically relevant substrates are thought to be sphingomyelin and/or lysophosphatidylcholine, which are common lipids in mammals. To better understand the substrate preference of these toxins, we used 31P-NMR to compare the activity of three related but phylogenetically diverse sicariid toxins against a diverse panel of sphingolipid and lysolipid substrates. Two of the three showed significantly faster turnover of sphingolipids over lysolipids, and all three showed a strong preference for positively charged (choline and/or ethanolamine) over neutral (glycerol and serine) head groups. Strikingly, however, the enzymes vary widely in their preference for choline, the head group of both sphingomyelin and lysophosphatidylcholine, versus ethanolamine. An enzyme from Sicarius terrosus showed a strong preference for ethanolamine over choline, while two paralogous enzymes from Loxosceles arizonica either preferred choline or showed no significant preference. Intrigued by the novel substrate preference of the Sicarius enzyme, we solved its crystal structure at 2.1 A resolution. The evolution of variable substrate specificity may help explain the reduced dermonecrotic potential of some natural toxin variants, because mammalian sphingolipids use primarily choline as a positively charged head group; it may also be relevant for sicariid predatory behavior, because ethanolamine-containing sphingolipids are common in insect prey. Variable Substrate Preference Among Phospholipase D Toxins From Sicariid Spiders.,Lajoie DM, Roberts SA, Zobel-Thropp PA, Delahaye JL, Bandarian V, Binford GJ, Cordes MH J Biol Chem. 2015 Mar 9. pii: jbc.M115.636951. PMID:25752604[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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