Molecular basis of antimicrobial and insecticidal activity of floral defensins from the Solonaceae. The flowers of Solanaceous plants produce high levels of defensins that protect the reproductive tissues against potential damage from microorganisms. The presence of related defensins in mammals, insects and plants indicates that they are part of an ancient defence mechanism. The floral defensins are potent antifungal molecules and surprisingly also have insecticidal activity. The aim of this pro ....Molecular basis of antimicrobial and insecticidal activity of floral defensins from the Solonaceae. The flowers of Solanaceous plants produce high levels of defensins that protect the reproductive tissues against potential damage from microorganisms. The presence of related defensins in mammals, insects and plants indicates that they are part of an ancient defence mechanism. The floral defensins are potent antifungal molecules and surprisingly also have insecticidal activity. The aim of this project is to understand the molecular basis of the antifungal and insecticide activity and to use this knowledge to produce improved molecules for crop protection.Read moreRead less
The effect of nitrogen monoxide on intracellular iron metabolism. We discovered that the crucial signalling molecule nitrogen monoxide (NO) mediates iron (Fe) and glutathione (GSH) release by the transporter MRP1 probably as an NO-Fe-GSH complex [DR(2006) PNAS USA 103:7670-5]. During our current ARC grant we have markedly extended these findings by showing that another molecule, GST Pi and MRP1 form part of a coordinated system that stores and transports NO as complexes of Fe and GSH, markedly e ....The effect of nitrogen monoxide on intracellular iron metabolism. We discovered that the crucial signalling molecule nitrogen monoxide (NO) mediates iron (Fe) and glutathione (GSH) release by the transporter MRP1 probably as an NO-Fe-GSH complex [DR(2006) PNAS USA 103:7670-5]. During our current ARC grant we have markedly extended these findings by showing that another molecule, GST Pi and MRP1 form part of a coordinated system that stores and transports NO as complexes of Fe and GSH, markedly extending NO half-life from milliseconds to hours. This has broad implications for understanding NO activity in many processes which have major vital health implications, including tumour cell killing by macrophages and blood pressure control.Read moreRead less
The Effect of Nitrogen Monoxide on Intracellular Iron Metabolism. For the first time, we discovered that nitric oxide (NO) is actively transported from cells by a protein that is known to also transport glutathione (GSH). This is important, as NO was thought to passively diffuse from cells. Active transport overcomes the problems of diffusion which is inefficient and non-targeted. Moreover, NO is released as a complex with iron and GSH which markedly increases its half-life. These findings have ....The Effect of Nitrogen Monoxide on Intracellular Iron Metabolism. For the first time, we discovered that nitric oxide (NO) is actively transported from cells by a protein that is known to also transport glutathione (GSH). This is important, as NO was thought to passively diffuse from cells. Active transport overcomes the problems of diffusion which is inefficient and non-targeted. Moreover, NO is released as a complex with iron and GSH which markedly increases its half-life. These findings have broad implications for understanding the activity of NO in many processes which have major health implications, including tumour cell killing by macrophages, blood pressure etc.Read moreRead less
The effect of nitrogen monoxide on intracellular iron metabolism. During our current ARC grant we discovered a novel relationship between energy metabolism and NO-mediated Fe efflux and showed that glutathione (GSH) is vital for this release mechanism (DR5,6). Intriguingly, this transport process is part of the cytotoxic effector machinery of activated macrophages against tumours, and requires further elucidation. We also showed that CO affects Fe metabolism by binding to Fe, and CO may modulate ....The effect of nitrogen monoxide on intracellular iron metabolism. During our current ARC grant we discovered a novel relationship between energy metabolism and NO-mediated Fe efflux and showed that glutathione (GSH) is vital for this release mechanism (DR5,6). Intriguingly, this transport process is part of the cytotoxic effector machinery of activated macrophages against tumours, and requires further elucidation. We also showed that CO affects Fe metabolism by binding to Fe, and CO may modulate NO's function. We will:-
(1) Examine if NO-mediated Fe release results in GSH efflux
(2) Identify the mechanism of NO-mediated Fe efflux.
(3) Assess the effect of inducing haem oxygenase 1 on Fe metabolism
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Membrane Attack Complex / Perforin like proteins in Defence, Attack and Developmental Biology. This proposal will result in a major advancement of knowledge, for example, in our understanding of the emerging links between immunity and development as well as the role and mechanism of function of the pore forming family of MACPF proteins in host defence, attack, embryo development and diseases such as cancer. These data will be crucial for developing approaches to control unwanted MACPF function, ....Membrane Attack Complex / Perforin like proteins in Defence, Attack and Developmental Biology. This proposal will result in a major advancement of knowledge, for example, in our understanding of the emerging links between immunity and development as well as the role and mechanism of function of the pore forming family of MACPF proteins in host defence, attack, embryo development and diseases such as cancer. These data will be crucial for developing approaches to control unwanted MACPF function, for example in disease such as diabetes or transplant rejection. Furthermore, a detailed understanding of how MACPF proteins assemble into rings and punch holes in membranes will facilitate the development of these proteins as technological tools.Read moreRead less
Delineating the role of the GxxxG motif in transmembrane protein metabolism. This study will define how a well defined motif involved in transmembrane interactions affects the metabolism of proteins. Since this motif is present in proteins involved in Alzheimer's disease it has potential benefits for community health and combating ageing.
Searching for novel protein domains: A bioinformatic analysis of whole proteomes. The functional annotation of the set of proteins encoded by a whole genome (the "proteome") is a crucial component of genome research. The aim of this project is to extend the functional and structural annotation of large protein databases by identifying novel protein domain families and building a novel domain library. Our approach is semi-automated and fast, thanks to execution in the fastest parallel supercom ....Searching for novel protein domains: A bioinformatic analysis of whole proteomes. The functional annotation of the set of proteins encoded by a whole genome (the "proteome") is a crucial component of genome research. The aim of this project is to extend the functional and structural annotation of large protein databases by identifying novel protein domain families and building a novel domain library. Our approach is semi-automated and fast, thanks to execution in the fastest parallel supercomputer in Australia available at the Victorian Partnership for Advanced Computing. Our preliminary data demonstrates that our method is feasible.Read moreRead less
Autophagy and the nucleus. Autophagy is a degradation pathway that is essential for survival, internal change (differentiation and development) and maintenance of physiological equilibrium (homeostasis). Moreover autophagy serves to protect higher organisms against infections, cancer and neurodegeneration. This project seeks to better understand the mechanisim by which parts of the nucleus can be degraded by autophagy and how this relates to diseases which may involve defects in, or abnormal deg ....Autophagy and the nucleus. Autophagy is a degradation pathway that is essential for survival, internal change (differentiation and development) and maintenance of physiological equilibrium (homeostasis). Moreover autophagy serves to protect higher organisms against infections, cancer and neurodegeneration. This project seeks to better understand the mechanisim by which parts of the nucleus can be degraded by autophagy and how this relates to diseases which may involve defects in, or abnormal degradation of nuclear components. Benefit will accrue from a contribution to knowledge with future potential to impact on disease, as well as strengthening links with the international network working in the field of autophagy.Read moreRead less
Development of high-throughput in silico methods for protein structure determination by X-ray crystallography. This work will have major outcomes for structural biology research at a national and international level. The ability to perform MR calculations using an exhaustive set of search models will offer a timesaving of weeks to months in a typical successful structure determination. Further, significant insights will be gained into the use of high-performance GRID computing in protein struct ....Development of high-throughput in silico methods for protein structure determination by X-ray crystallography. This work will have major outcomes for structural biology research at a national and international level. The ability to perform MR calculations using an exhaustive set of search models will offer a timesaving of weeks to months in a typical successful structure determination. Further, significant insights will be gained into the use of high-performance GRID computing in protein structure determination by X-ray crystallography. This knowledge has considerable impact on our ability to undertake high quality structural biology research - a key area in the majority of biological research programmes. Read moreRead less
Protein methylation: a fundamental regulator of the interactome. Proteins are the functional molecules of the cell. They interact with each other to form small 'protein machines' that are part of large, complicated networks. This study will examine how the cell makes tiny changes to proteins, through the addition of one carbon and two hydrogen atoms, and how this is important in the regulation of protein interactions. The proteins of baker's yeast, a common model organism, will be studied here. ....Protein methylation: a fundamental regulator of the interactome. Proteins are the functional molecules of the cell. They interact with each other to form small 'protein machines' that are part of large, complicated networks. This study will examine how the cell makes tiny changes to proteins, through the addition of one carbon and two hydrogen atoms, and how this is important in the regulation of protein interactions. The proteins of baker's yeast, a common model organism, will be studied here. However, the findings will be directly relevant to understanding the function of many proteins in plants, animals and man.
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