The allosteric activation mechanism of a phospholipase A2-like toxin from Bothrops jararacussu venom: a dynamic description

Abstract

The activation process of phospholipase A2-like (PLA2-like) toxins is a key step in their molecular mechanism, which involves oligomeric changes leading to the exposure of specific sites. Few studies have focused on the characterization of allosteric activators and the features that distinguish them from inhibitors. Herein, a comprehensive study with the BthTX-I toxin from Bothrops jararacussu venom bound or unbound to α-tocopherol (αT) was carried out. The oligomerization state of BthTX-I bound or unbound to αT in solution was studied and indicated that the toxin is predominantly monomeric but tends to oligomerize when complexed with αT. In silico molecular simulations showed the toxin presents higher conformational changes in the absence of αT, which suggests that it is important to stabilize the structure of the toxin. The transition between the two states (active/inactive) was also studied, showing that only the unbound BthTX-I system could migrate to the inactive state. In contrast, the presence of αT induces the toxin to leave the inactive state, guiding it towards the active state, with more regions exposed to the solvent, particularly its active site. Finally, the structural determinants necessary for a molecule to be an inhibitor or activator were analyzed in light of the obtained results.

Substrate Access Mechanism in a Novel Membrane-Bound Phospholipase A of Pseudomonas aeruginosa Concordant with Specificity and Regioselectivity

“…Dimer–monomer transitions regulate the activity of several membrane-bound phospholipases, including PLA 1 and phospholipase A 2 (PLA 2 ). − Previously, we showed that PlaF becomes active due to a dimer-to-monomer transition followed by tilting of the monomer in the membrane, resulting in t-PlaF A being the active configuration of PlaF . Here, we addressed the questions of how membrane-bound substrates reach the active site of PlaF A and how the characteristics of the active site tunnels determine the activity, specificity, and regioselectivity of PlaF for medium-chain substrates.…”

Viper Venom Phospholipase A2 Database: The Structural and Functional Anatomy of a Primary Toxin in Envenomation

“…The Role of the N-Terminal Region for Membrane Binding and Enzymatic Activity vvPLA2s contain an α-helical N-terminal region believed to be implicated in critical functions, such as membrane binding, and vital structural areas, such as the substratebinding hydrophobic channel. X-ray structures of PLA2s from the Indian cobra (Naja naja) [47] and the European bee (Apis mellifera) [48] venoms and from human [49] and pig (sus Monomeric and dimeric vvPLA2s are the most common quaternary structures found via X-ray crystallography [19,[34][35][36], and they are supposed to be the most common in solution too.…”

“…Monomeric and dimeric vvPLA2s are the most common quaternary structures found via X-ray crystallography [ 19 , 34 , 35 , 36 ], and they are supposed to be the most common in solution too.…”

Substrate access mechanism in a novel membrane-bound phospholipase A of Pseudomonas aeruginosa concordant with specificity and regioselectivity

“…Dimer-monomer transitions regulate the activity of several membrane-bound phospholipases, including PLA 1 , and PLA 2 [45][46][47][48][49][50][51][52]. Previously, we showed that PlaF becomes active due to a dimer-to-monomer transition followed by tilting of the monomer in the membrane, resulting in t-PlaF A being the active configuration of PlaF [19].…”