4dcf

Structural highlights

Function

PA2H1_BOTBZ Snake venom phospholipase A2 homolog that lacks enzymatic activity. Is myotoxic and displays edema-inducing activities in mouse paw (PubMed:18602430). Also displays cytotoxic activity against some cell lines, and antimicrobial activities against E.coli, C.albicans and Leishmania (PubMed:18602430). A model of myotoxic mechanism has been proposed: an apo Lys49-PLA2 is activated by the entrance of a hydrophobic molecule (e.g. fatty acid) at the hydrophobic channel of the protein leading to a reorientation of a monomer (PubMed:24145104). This reorientation causes a transition between 'inactive' to 'active' states, causing alignment of C-terminal and membrane-docking sites (MDoS) side-by-side and putting the membrane-disruption sites (MDiS) in the same plane, exposed to solvent and in a symmetric position for both monomers (PubMed:24145104). The MDoS region stabilizes the toxin on membrane by the interaction of charged residues with phospholipid head groups (PubMed:24145104). Subsequently, the MDiS region destabilizes the membrane with penetration of hydrophobic residues (PubMed:24145104). This insertion causes a disorganization of the membrane, allowing an uncontrolled influx of ions (i.e. calcium and sodium), and eventually triggering irreversible intracellular alterations and cell death (PubMed:24145104).^{[1] [2]}

References

1. ↑ Costa TR, Menaldo DL, Oliveira CZ, Santos-Filho NA, Teixeira SS, Nomizo A, Fuly AL, Monteiro MC, de Souza BM, Palma MS, Stabeli RG, Sampaio SV, Soares AM. Myotoxic phospholipases A(2) isolated from Bothrops brazili snake venom and synthetic peptides derived from their C-terminal region: cytotoxic effect on microorganism and tumor cells. Peptides. 2008 Oct;29(10):1645-56. doi: 10.1016/j.peptides.2008.05.021. Epub 2008, Jun 5. PMID:18602430 doi:http://dx.doi.org/10.1016/j.peptides.2008.05.021
2. ↑ Fernandes CA, Comparetti EJ, Borges RJ, Huancahuire-Vega S, Ponce-Soto LA, Marangoni S, Soares AM, Fontes MR. Structural bases for a complete myotoxic mechanism: Crystal structures of two non-catalytic phospholipases A-like from Bothrops brazili venom. Biochim Biophys Acta. 2013 Oct 18;1834(12):2772-2781. doi:, 10.1016/j.bbapap.2013.10.009. PMID:24145104 doi:http://dx.doi.org/10.1016/j.bbapap.2013.10.009