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Title: Membrane perturbing properties of toxin mycolactone from Mycobacterium ulcerans

Abstract

Mycolactone is the exotoxin produced by Mycobacterium ulcerans and is the virulence factor behind the neglected tropical disease Buruli ulcer. The toxin has a broad spectrum of biological effects within the host organism, stemming from its interaction with at least two molecular targets and the inhibition of protein uptake into the endoplasmic reticulum. Although it has been shown that the toxin can passively permeate into host cells, it is clearly lipophilic. Association with lipid carriers would have substantial implications for the toxin’s distribution within a host organism, delivery to cellular targets, diagnostic susceptibility, and mechanisms of pathogenicity. Yet the toxin’s interactions with, and distribution in, lipids are unknown. Herein we have used coarse-grained molecular dynamics simulations, guided by all-atom simulations, to study the interaction of mycolactone with pure and mixed lipid membranes. Using established techniques, we calculated the toxin’s preferential localization, membrane translocation, and impact on membrane physical and dynamical properties. The computed water-octanol partition coefficient indicates that mycolactone prefers to be in an organic phase rather than in an aqueous environment. Our results show that in a solvated membrane environment the exotoxin mainly localizes in the water-membrane interface, with a preference for the glycerol moiety of lipids, consistent withmore » the reported studies that found it in lipid extracts of the cell. The calculated association constant to the model membrane is similar to the reported association constant for Wiskott-Aldrich syndrome protein. Mycolactone is shown to modify the physical properties of membranes, lowering the transition temperature, compressibility modulus, and critical line tension at which pores can be stabilized. It also shows a tendency to behave as a linactant, a molecule that localizes at the boundary between different fluid lipid domains in membranes and promotes inter-mixing of domains. This property has implications for the toxin’s cellular access, T-cell immunosuppression, and therapeutic potential.« less

Authors:
ORCiD logo [1];  [1];  [1]; ORCiD logo [2];  [1]
+ Show Author Affiliations
  1. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  2. Univ. of Chicago, IL (United States). Dept. of Chemistry
Publication Date:
Research Org.:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE; National Inst. of Health (NIH) (United States)
OSTI Identifier:
1440469
Report Number(s):
LA-UR-14-29038
Journal ID: ISSN 1553-7358
Grant/Contract Number:  
AC52-06NA25396; P50GM085273; R37GM035556; R01-AI113266
Resource Type:
Accepted Manuscript
Journal Name:
PLoS Computational Biology (Online)
Additional Journal Information:
Journal Name: PLoS Computational Biology (Online); Journal Volume: 14; Journal Issue: 2; Journal ID: ISSN 1553-7358
Publisher:
Public Library of Science
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Biological Science

Citation Formats

Lopez, Cesar A., Unkefer, Clifford J., Swanson, Basil I., Swanson, Jessica M. J., and Gnanakaran, S. Membrane perturbing properties of toxin mycolactone from Mycobacterium ulcerans. United States: N. p., 2018. Web. doi:10.1371/journal.pcbi.1005972.
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Lopez, Cesar A., Unkefer, Clifford J., Swanson, Basil I., Swanson, Jessica M. J., & Gnanakaran, S. Membrane perturbing properties of toxin mycolactone from Mycobacterium ulcerans. United States. https://doi.org/10.1371/journal.pcbi.1005972
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Lopez, Cesar A., Unkefer, Clifford J., Swanson, Basil I., Swanson, Jessica M. J., and Gnanakaran, S. Mon . "Membrane perturbing properties of toxin mycolactone from Mycobacterium ulcerans". United States. https://doi.org/10.1371/journal.pcbi.1005972. https://www.osti.gov/servlets/purl/1440469.
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@article{osti_1440469,
title = {Membrane perturbing properties of toxin mycolactone from Mycobacterium ulcerans},
author = {Lopez, Cesar A. and Unkefer, Clifford J. and Swanson, Basil I. and Swanson, Jessica M. J. and Gnanakaran, S.},
abstractNote = {Mycolactone is the exotoxin produced by Mycobacterium ulcerans and is the virulence factor behind the neglected tropical disease Buruli ulcer. The toxin has a broad spectrum of biological effects within the host organism, stemming from its interaction with at least two molecular targets and the inhibition of protein uptake into the endoplasmic reticulum. Although it has been shown that the toxin can passively permeate into host cells, it is clearly lipophilic. Association with lipid carriers would have substantial implications for the toxin’s distribution within a host organism, delivery to cellular targets, diagnostic susceptibility, and mechanisms of pathogenicity. Yet the toxin’s interactions with, and distribution in, lipids are unknown. Herein we have used coarse-grained molecular dynamics simulations, guided by all-atom simulations, to study the interaction of mycolactone with pure and mixed lipid membranes. Using established techniques, we calculated the toxin’s preferential localization, membrane translocation, and impact on membrane physical and dynamical properties. The computed water-octanol partition coefficient indicates that mycolactone prefers to be in an organic phase rather than in an aqueous environment. Our results show that in a solvated membrane environment the exotoxin mainly localizes in the water-membrane interface, with a preference for the glycerol moiety of lipids, consistent with the reported studies that found it in lipid extracts of the cell. The calculated association constant to the model membrane is similar to the reported association constant for Wiskott-Aldrich syndrome protein. Mycolactone is shown to modify the physical properties of membranes, lowering the transition temperature, compressibility modulus, and critical line tension at which pores can be stabilized. It also shows a tendency to behave as a linactant, a molecule that localizes at the boundary between different fluid lipid domains in membranes and promotes inter-mixing of domains. This property has implications for the toxin’s cellular access, T-cell immunosuppression, and therapeutic potential.},
doi = {10.1371/journal.pcbi.1005972},
journal = {PLoS Computational Biology (Online)},
number = 2,
volume = 14,
place = {United States},
year = {Mon Feb 05 00:00:00 EST 2018},
month = {Mon Feb 05 00:00:00 EST 2018}
}
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Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
https://doi.org/10.1371/journal.pcbi.1005972
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Cited by: 16 works
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Figures / Tables:

Fig 1 Fig 1: Mycolactone in model lipid membrane. A) All-atom and coarse-grained representations of diC16-PC (cyan and green) and mycolactone (cyan and yellow). The atomistic representation is characterized by an 8-undecenolide region (blue box), the C12-C20 northern fragment (red box), and the pentanoic acid ester southern fragment (yellow box). The CGmore » representation can be described in terms of the head and tail regions. Different bead types (N1-N13) capture the general topology of the CG resolution, according to the definition of MARTINI force field (see Methods). B) The CG set-up of pure diC16-PC bilayer system in combination with 5% mycolactone. Notice that the simulation box is enclosed by the gray square. C) Cross section snapshot of the equilibrated membrane simulation. For clarity, diC16-PC lipid has been depicted by its head group (orange), the glycerol moiety (red) and the aliphatic tails (dark gray). D) Histograms correspond to probability distribution of two common configurations of mycolactone in lipid bilayer; either at the surface (black) or spanning the bilayer (red). The distributions are calculated as function of the distance between CG beads N1 and N13 for the bilayer system with 5% mycolactone as shown in the set-up of panel B. The dashed lines show the accumulation of population of these two configurations. Insets in both C and D (enclosed in circles) show representative configurations from all atom MD simulations.« less
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journal, December 2010

Efficient Determination of Protein–Protein Standard Binding Free Energies from First Principles
journal, July 2013

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The nucleotide switch in Cdc42 modulates coupling between the GTPase-binding and allosteric equilibria of Wiskott-Aldrich syndrome protein
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journal, January 2011

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Mycolactone impairs T cell homing by suppressing microRNA control of L-selectin expression
journal, July 2011

  • Guenin-Mace, L.; Carrette, F.; Asperti-Boursin, F.
  • Proceedings of the National Academy of Sciences, Vol. 108, Issue 31
  • DOI: 10.1073/pnas.1016496108

Membrane bending is critical for the stability of voltage sensor segments in the membrane
journal, June 2012

  • Callenberg, Keith M.; Latorraca, Naomi R.; Grabe, Michael
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GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit
journal, February 2013

Revisiting Buruli ulcer
journal, September 2015

  • Yotsu, Rie R.; Murase, Chiaki; Sugawara, Mariko
  • The Journal of Dermatology, Vol. 42, Issue 11
  • DOI: 10.1111/1346-8138.13049

Modulation of the host immune response by a transient intracellular stage of Mycobacterium ulcerans: the contribution of endogenous mycolactone toxin
journal, August 2005

Shaping mycolactone for therapeutic use against inflammatory disorders
journal, May 2015

  • Guenin-Macé, Laure; Baron, Ludivine; Chany, Anne-Caroline
  • Science Translational Medicine, Vol. 7, Issue 289
  • DOI: 10.1126/scitranslmed.aab0458

Mycobacterium ulcerans infections cause progressive muscle atrophy and dysfunction, and mycolactone impairs satellite cell proliferation
journal, March 2011

  • Houngbédji, Germain Mabèrou; Bouchard, Patrice; Frenette, Jérôme
  • American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 300, Issue 3
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Structure of lipid bilayers
text, January 2000

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Detection of Mycolactone A/B in Mycobacterium ulcerans–Infected Human Tissue
journal, January 2010

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Mycolactone Diffuses into the Peripheral Blood of Buruli Ulcer Patients - Implications for Diagnosis and Disease Monitoring
journal, July 2011

Antibody-Mediated Neutralization of the Exotoxin Mycolactone, the Main Virulence Factor Produced by Mycobacterium ulcerans
journal, June 2016

  • Dangy, Jean-Pierre; Scherr, Nicole; Gersbach, Philipp
  • PLOS Neglected Tropical Diseases, Vol. 10, Issue 6
  • DOI: 10.1371/journal.pntd.0004808

The potent effect of mycolactone on lipid membranes
journal, January 2018

Mycolactone Suppresses T Cell Responsiveness by Altering Both Early Signaling and Posttranslational Events
journal, December 2009

  • Boulkroun, Sheerazed; Guenin-Macé, Laure; Thoulouze, Maria-Isabel
  • The Journal of Immunology, Vol. 184, Issue 3
  • DOI: 10.4049/jimmunol.0902854
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    Works referencing / citing this record:

    Sec61 blockade by mycolactone: A central mechanism in Buruli ulcer disease: Mycolactone-driven Sec61 blockade and Buruli ulcer
    journal, August 2018

    Understanding the Significance of Biochemistry in the Storage, Handling, Purification, and Sampling of Amphiphilic Mycolactone
    journal, April 2019

    Computational Modeling of Realistic Cell Membranes
    journal, January 2019

    Understanding the Significance of Biochemistry in the Storage, Handling, Purification, and Sampling of Amphiphilic Mycolactone
    journal, April 2019

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