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Open AccessArticle

Molecular Mechanism by Which Cobra Venom Cardiotoxins Interact with the Outer Mitochondrial Membrane

1
STEM Program, Science Department, Chaoyang KaiWen Academy, Yard 46, 3rd Baoquan Street, Chaoyang District, Beijing 100018, China
2
Department of Computational and System Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA
3
Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15260, USA
4
Reno School of Medicine, Department of Pharmacology, University of Nevada, Reno, NV 89557, USA
*
Author to whom correspondence should be addressed.
Toxins 2020, 12(7), 425; https://doi.org/10.3390/toxins12070425
Received: 14 May 2020 / Revised: 23 June 2020 / Accepted: 26 June 2020 / Published: 27 June 2020
(This article belongs to the Special Issue Animal Venoms and Their Components: Molecular Mechanisms of Action)
Cardiotoxin CTII from Naja oxiana cobra venom translocates to the intermembrane space (IMS) of mitochondria to disrupt the structure and function of the inner mitochondrial membrane. At low concentrations, CTII facilitates ATP-synthase activity, presumably via the formation of non-bilayer, immobilized phospholipids that are critical in modulating ATP-synthase activity. In this study, we investigated the effects of another cardiotoxin CTI from Naja oxiana cobra venom on the structure of mitochondrial membranes and on mitochondrial-derived ATP synthesis. By employing robust biophysical methods including 31P-NMR and 1H-NMR spectroscopy, we analyzed the effects of CTI and CTII on phospholipid packing and dynamics in model phosphatidylcholine (PC) membranes enriched with 2.5 and 5.0 mol% of cardiolipin (CL), a phospholipid composition that mimics that in the outer mitochondrial membrane (OMM). These experiments revealed that CTII converted a higher percentage of bilayer phospholipids to a non-bilayer and immobilized state and both cardiotoxins utilized CL and PC molecules to form non-bilayer structures. Furthermore, in order to gain further understanding on how cardiotoxins bind to mitochondrial membranes, we employed molecular dynamics (MD) and molecular docking simulations to investigate the molecular mechanisms by which CTII and CTI interactively bind with an in silico phospholipid membrane that models the composition similar to the OMM. In brief, MD studies suggest that CTII utilized the N-terminal region to embed the phospholipid bilayer more avidly in a horizontal orientation with respect to the lipid bilayer and thereby penetrate at a faster rate compared with CTI. Molecular dynamics along with the Autodock studies identified critical amino acid residues on the molecular surfaces of CTII and CTI that facilitated the long-range and short-range interactions of cardiotoxins with CL and PC. Based on our compiled data and our published findings, we provide a conceptual model that explains a molecular mechanism by which snake venom cardiotoxins, including CTI and CTII, interact with mitochondrial membranes to alter the mitochondrial membrane structure to either upregulate ATP-synthase activity or disrupt mitochondrial function. View Full-Text
Keywords: cobra cardiotoxins; non-bilayer immobilized phospholipids; outer mitochondrial membrane; cardiolipin; phosphatidylcholine; ATP-synthase cobra cardiotoxins; non-bilayer immobilized phospholipids; outer mitochondrial membrane; cardiolipin; phosphatidylcholine; ATP-synthase
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Li, F.; Shrivastava, I.H.; Hanlon, P.; Dagda, R.K.; Gasanoff, E.S. Molecular Mechanism by Which Cobra Venom Cardiotoxins Interact with the Outer Mitochondrial Membrane. Toxins 2020, 12, 425.

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