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Naja naja oxiana cobra venom cytotoxins CTI and CTII disrupt mitochondrial membrane integrity: Implications for basic three-fingered cytotoxins

Gasanov, SE and Shrivastava, IH and Israilov, FS and Kim, AA and Rylova, KA and Zhang, B and Dagda, RK (2015) Naja naja oxiana cobra venom cytotoxins CTI and CTII disrupt mitochondrial membrane integrity: Implications for basic three-fingered cytotoxins. PLoS ONE, 10 (6).

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Abstract

Copyright © 2015 Gasanov et al. Cobra venom cytotoxins are basic three-fingered, amphipathic, non-enzymatic proteins that constitute a major fraction of cobra venom. While cytotoxins cause mitochondrial dysfunction in different cell types, the mechanisms by which cytotoxins bind to mitochondria remain unknown.We analyzed the abilities of CTI and CTII, S-type and P-type cytotoxins from Naja naja oxiana respectively, to associate with isolated mitochondrial fractions or with model membranes that simulate the mitochondrial lipid environment by using a myriad of biophysical techniques. Phosphorus-31 nuclear magnetic resonance (<sup>31</sup>P-NMR) spectroscopy data suggest that both cytotoxins bind to isolated mitochondrial fractions and promote the formation of aberrant non-bilayer structures.We then hypothesized that CTI and CTII bind to cardiolipin (CL) to disrupt mitochondrial membranes. Collectively, <sup>31</sup>P-NMR, electron paramagnetic resonance (EPR), proton NMR (<sup>1</sup>H-NMR), deuterium NMR (<sup>2</sup>H-NMR) spectroscopy, differential scanning calorimetry, and erythrosine phosphorescence assays suggest that CTI and CTII bind to CL to generate non-bilayer structures and promote the permeabilization, dehydration and fusion of large unilamellar phosphatidylcholine (PC) liposomes enriched with CL. On the other hand, CTII but not CTI caused biophysical alterations of large unilamellar PC liposomes enriched with phosphatidylserine (PS). Mechanistically, single molecule docking simulations identified putative CL, PS and PC binding sites in CTI and CTII. While the predicted binding sites for PS and PC share a high number of interactive amino acid residues in CTI and CTII, the CL biding sites in CTII and CTI are more divergent as it contains additional interactive amino acid residues. Overall, our data suggest that cytotoxins physically associate with mitochondrial membranes by binding to CL to disrupt mitochondrial structural integrity.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Gasanov, SE
Shrivastava, IHihs2@pitt.eduIHS2
Israilov, FS
Kim, AA
Rylova, KA
Zhang, B
Dagda, RK
Date: 19 June 2015
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS ONE
Volume: 10
Number: 6
DOI or Unique Handle: 10.1371/journal.pone.0129248
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Computational and Systems Biology
Refereed: Yes
Date Deposited: 28 Jun 2016 18:37
Last Modified: 26 Jan 2019 10:55
URI: http://d-scholarship.pitt.edu/id/eprint/28435

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