Surgical Diagnostics Pty Ltd.

Roseville, Australia

Surgical Diagnostics Pty Ltd.

Roseville, Australia

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Valenzuela S.M.,University of Technology, Sydney | Alkhamici H.,University of Technology, Sydney | Brown L.J.,Macquarie University | Almond O.C.,University of Technology, Sydney | And 8 more authors.
PLoS ONE | Year: 2013

The Chloride Intracellular ion channel protein CLIC1 has the ability to spontaneously insert into lipid membranes from a soluble, globular state. The precise mechanism of how this occurs and what regulates this insertion is still largely unknown, although factors such as pH and redox environment are known contributors. In the current study, we demonstrate that the presence and concentration of cholesterol in the membrane regulates the spontaneous insertion of CLIC1 into the membrane as well as its ion channel activity. The study employed pressure versus area change measurements of Langmuir lipid monolayer films; and impedance spectroscopy measurements using tethered bilayer membranes to monitor membrane conductance during and following the addition of CLIC1 protein. The observed cholesterol dependent behaviour of CLIC1 is highly reminiscent of the cholesterol-dependent-cytolysin family of bacterial pore-forming proteins, suggesting common regulatory mechanisms for spontaneous protein insertion into the membrane bilayer. © 2013 Valenzuela et al.


Hoiles W.,University of British Columbia | Gupta R.,University of British Columbia | Cornell B.,Surgical Diagnostics Pty. Ltd. | Cranfield C.,University of Technology, Sydney | Krishnamurthy V.,Cornell University
PLoS ONE | Year: 2016

Tethered bilayer lipid membranes (tBLMs) provide a stable platform for modeling the dynamics and order of biological membranes where the tethers mimic the cytoskeletal supports present in biological cell membranes. In this paper coarse-grained molecular dynamics (CGMD) is applied to study the effects of tethers on lipid membrane properties. Using results from the CGMD model and the overdamped Fokker-Planck equation, we show that the diffusion tensor and particle density of water in the tBLM is spatially dependent. Further, it is shown that the membrane thickness, lipid diffusion, defect density, free energy of lipid flip-flop, and membrane dielectric permittivity are all dependent on the tether density. The numerically computed results from the CGMD model are in agreement with the experimentally measured results from tBLMs containing different tether densities and lipids derived from Archaebacteria. Additionally, using experimental measurements from Escherichia coli bacteria and Saccharomyces Cerevisiae yeast tethered membranes, we illustrate how previous molecular dynamics results can be combined with the proposed model to estimate the dielectric permittivity and defect density of these membranes as a function of tether density. © 2016 Hoiles et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


PubMed | University of Technology, Sydney and Surgical Diagnostics Pty Ltd.
Type: Journal Article | Journal: Membranes | Year: 2016

The Chloride Intracellular Ion Channel (CLIC) family consists of six conserved proteins in humans. These are a group of enigmatic proteins, which adopt both a soluble and membrane bound form. CLIC1 was found to be a metamorphic protein, where under specific environmental triggers it adopts more than one stable reversible soluble structural conformation. CLIC1 was found to spontaneously insert into cell membranes and form chloride ion channels. However, factors that control the structural transition of CLIC1 from being an aqueous soluble protein into a membrane bound protein have yet to be adequately described. Using tethered bilayer lipid membranes and electrical impedance spectroscopy system, herein we demonstrate that CLIC1 ion channel activity is dependent on the type and concentration of sterols in bilayer membranes. These findings suggest that membrane sterols play an essential role in CLIC1s acrobatic switching from a globular soluble form to an integral membrane form, promoting greater ion channel conductance in membranes. What remains unclear is the precise nature of this regulation involving membrane sterols and ultimately determining CLIC1s membrane structure and function as an ion channel. Furthermore, our impedance spectroscopy results obtained using CLIC1 mutants, suggest that the residue Cys24 is not essential for CLIC1s ion channel function. However Cys24 does appear important for optimal ion channel activity. We also observe differences in conductance between CLIC1 reduced and oxidized forms when added to our tethered membranes. Therefore, we conclude that both membrane sterols and redox play a role in the ion channel activity of CLIC1.


PubMed | University of British Columbia, Cornell University, University of Technology, Sydney and Surgical Diagnostics Pty Ltd.
Type: Journal Article | Journal: PloS one | Year: 2016

Tethered bilayer lipid membranes (tBLMs) provide a stable platform for modeling the dynamics and order of biological membranes where the tethers mimic the cytoskeletal supports present in biological cell membranes. In this paper coarse-grained molecular dynamics (CGMD) is applied to study the effects of tethers on lipid membrane properties. Using results from the CGMD model and the overdamped Fokker-Planck equation, we show that the diffusion tensor and particle density of water in the tBLM is spatially dependent. Further, it is shown that the membrane thickness, lipid diffusion, defect density, free energy of lipid flip-flop, and membrane dielectric permittivity are all dependent on the tether density. The numerically computed results from the CGMD model are in agreement with the experimentally measured results from tBLMs containing different tether densities and lipids derived from Archaebacteria. Additionally, using experimental measurements from Escherichia coli bacteria and Saccharomyces Cerevisiae yeast tethered membranes, we illustrate how previous molecular dynamics results can be combined with the proposed model to estimate the dielectric permittivity and defect density of these membranes as a function of tether density.


Martinac B.,Victor Chang Cardiac Research Institute | Martinac B.,University of New South Wales | Nomura T.,Victor Chang Cardiac Research Institute | Chi G.,University of Queensland | And 14 more authors.
Antioxidants and Redox Signaling | Year: 2014

Significance: Sensations of touch and hearing are manifestations of mechanical contact and air pressure acting on touch receptors and hair cells of the inner ear, respectively. In bacteria, osmotic pressure exerts a significant mechanical force on their cellular membrane. Bacteria have evolved mechanosensitive (MS) channels to cope with excessive turgor pressure resulting from a hypo-osmotic shock. MS channel opening allows the expulsion of osmolytes and water, thereby restoring normal cellular turgor and preventing cell lysis. Recent Advances: As biological force-sensing systems, MS channels have been identified as the best examples of membrane proteins coupling molecular dynamics to cellular mechanics. The bacterial MS channel of large conductance (MscL) and MS channel of small conductance (MscS) have been subjected to extensive biophysical, biochemical, genetic, and structural analyses. These studies have established MscL and MscS as model systems for mechanosensory transduction. Critical Issues: In recent years, MS ion channels in mammalian cells have moved into focus of mechanotransduction research, accompanied by an increased awareness of the role they may play in the pathophysiology of diseases, including cardiac hypertrophy, muscular dystrophy, or Xerocytosis. Future Directions: A recent exciting development includes the molecular identification of Piezo proteins, which function as nonselective cation channels in mechanosensory transduction associated with senses of touch and pain. Since research on Piezo channels is very young, applying lessons learned from studies of bacterial MS channels to establishing the mechanism by which the Piezo channels are mechanically activated remains one of the future challenges toward a better understanding of the role that MS channels play in mechanobiology. Antioxid. Redox Signal. 20, 952-969. © 2014 Mary Ann Liebert, Inc.


Monfared S.M.,University of British Columbia | Krishnamurthy V.,University of British Columbia | Cornell B.C.,Surgical Diagnostics Pty Ltd.
Proceedings of the IEEE Conference on Decision and Control | Year: 2010

This paper deals with the construction and analysis of distributed dynamical models for a novel biosensor that exploits the molecular switching mechanism of biological ion channels. The rate of change of the concentration of the chemical species in the biosensor are given by a system of nonlinear ordinary differential equations in the reaction-rate limited region of operation. When the transport rate of analyte to the biosensor surface is comparable to the intrinsic reaction rates, the dynamics of the biosensor are explained accurately using a two dimensional advection diffusion parabolic partial differential equation. When the rate of transport of analyte to the biosensor surface is much slower than the intrinsic reaction rates the biosensor is said to be operating under mass transport limited conditions. Under these conditions a system of coupled ordinary differential equations and the mass transport coefficient model the dynamics of the biosensor accurately. The equivalent mathematical models are shown to produce accurate data under the required operating conditions by comparison with experimental data. ©2010 IEEE.

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