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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]
  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 Lab. (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.
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. doi:10.1371/journal.pcbi.1005972.
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. doi:10.1371/journal.pcbi.1005972. https://www.osti.gov/servlets/purl/1440469.
@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 = {2018},
month = {2}
}

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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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