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

Cardiotoxin CTII from <i>Naja</i><i> </i><i>oxiana</i> 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 activit...

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Main Authors: Feng Li, Indira H. Shrivastava, Paul Hanlon, Ruben K. Dagda, Edward S. Gasanoff
Format: Article
Language:English
Published: MDPI AG 2020-06-01
Series:Toxins
Subjects:
Online Access:https://www.mdpi.com/2072-6651/12/7/425
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spelling doaj-8ab31905fe7a4e0394f5b1e0401914e02020-11-25T03:19:29ZengMDPI AGToxins2072-66512020-06-011242542510.3390/toxins12070425Molecular Mechanism by which Cobra Venom Cardiotoxins Interact with the Outer Mitochondrial MembraneFeng Li0Indira H. Shrivastava1Paul Hanlon2Ruben K. Dagda3Edward S. Gasanoff4STEM Program, Science Department, Chaoyang KaiWen Academy, Yard 46, 3rd Baoquan Street, Chaoyang District, Beijing 100018, ChinaDepartment of Computational and System Biology, University of Pittsburgh, PA 15260, USASTEM Program, Science Department, Chaoyang KaiWen Academy, Yard 46, 3rd Baoquan Street, Chaoyang District, Beijing 100018, ChinaReno School of Medicine, Department of Pharmacology, University of Nevada, Reno, NV 89557, USASTEM Program, Science Department, Chaoyang KaiWen Academy, Yard 46, 3rd Baoquan Street, Chaoyang District, Beijing 100018, ChinaCardiotoxin CTII from <i>Naja</i><i> </i><i>oxiana</i> 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 <i>Naja</i><i> </i><i>oxiana</i> cobra venom on the structure of mitochondrial membranes and on mitochondrial-derived ATP synthesis. By employing robust biophysical methods including <sup>31</sup>P-NMR and <sup>1</sup>H-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 <i>in silico</i> 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.https://www.mdpi.com/2072-6651/12/7/425cobra cardiotoxinsnon-bilayer immobilized phospholipidsouter mitochondrial membranecardiolipinphosphatidylcholineATP-synthase
collection DOAJ
language English
format Article
sources DOAJ
author Feng Li
Indira H. Shrivastava
Paul Hanlon
Ruben K. Dagda
Edward S. Gasanoff
spellingShingle Feng Li
Indira H. Shrivastava
Paul Hanlon
Ruben K. Dagda
Edward S. Gasanoff
Molecular Mechanism by which Cobra Venom Cardiotoxins Interact with the Outer Mitochondrial Membrane
Toxins
cobra cardiotoxins
non-bilayer immobilized phospholipids
outer mitochondrial membrane
cardiolipin
phosphatidylcholine
ATP-synthase
author_facet Feng Li
Indira H. Shrivastava
Paul Hanlon
Ruben K. Dagda
Edward S. Gasanoff
author_sort Feng Li
title Molecular Mechanism by which Cobra Venom Cardiotoxins Interact with the Outer Mitochondrial Membrane
title_short Molecular Mechanism by which Cobra Venom Cardiotoxins Interact with the Outer Mitochondrial Membrane
title_full Molecular Mechanism by which Cobra Venom Cardiotoxins Interact with the Outer Mitochondrial Membrane
title_fullStr Molecular Mechanism by which Cobra Venom Cardiotoxins Interact with the Outer Mitochondrial Membrane
title_full_unstemmed Molecular Mechanism by which Cobra Venom Cardiotoxins Interact with the Outer Mitochondrial Membrane
title_sort molecular mechanism by which cobra venom cardiotoxins interact with the outer mitochondrial membrane
publisher MDPI AG
series Toxins
issn 2072-6651
publishDate 2020-06-01
description Cardiotoxin CTII from <i>Naja</i><i> </i><i>oxiana</i> 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 <i>Naja</i><i> </i><i>oxiana</i> cobra venom on the structure of mitochondrial membranes and on mitochondrial-derived ATP synthesis. By employing robust biophysical methods including <sup>31</sup>P-NMR and <sup>1</sup>H-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 <i>in silico</i> 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.
topic cobra cardiotoxins
non-bilayer immobilized phospholipids
outer mitochondrial membrane
cardiolipin
phosphatidylcholine
ATP-synthase
url https://www.mdpi.com/2072-6651/12/7/425
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