Function and modulation of the protein quality control network in mammalian mitochondria. This project has potential technological benefit in the areas of biotechnology and molecular medicine especially in relation to age-related cellular degeneration. As a result of our research outputs, strategies could be developed to either delay the onset or reduce the severity of diseases related to mitochondrial dysfunction. Training research scientists of the future, forms an integral part of our researc ....Function and modulation of the protein quality control network in mammalian mitochondria. This project has potential technological benefit in the areas of biotechnology and molecular medicine especially in relation to age-related cellular degeneration. As a result of our research outputs, strategies could be developed to either delay the onset or reduce the severity of diseases related to mitochondrial dysfunction. Training research scientists of the future, forms an integral part of our research program and our association with world leaders in the field provide excellent opportunity for exchange of personnel, ideas and emerging methodologies. This project will lead the way in this field and consequently will expand Australia's reputation at the forefront of scientific advancement. Read moreRead less
AAA+ proteases: substrate binding, translocation and modulation by novel adaptor proteins. Protein quality control is essential for the proper maintenance of the cell. It ensures the correct folding of newly synthesised proteins, the refolding or degradation of misfolded and aggregated proteins, and the controlled degradation of regulatory proteins. These functions are collectively performed by molecular chaperones and proteases. This project will define the molecular basis of substrate selectiv ....AAA+ proteases: substrate binding, translocation and modulation by novel adaptor proteins. Protein quality control is essential for the proper maintenance of the cell. It ensures the correct folding of newly synthesised proteins, the refolding or degradation of misfolded and aggregated proteins, and the controlled degradation of regulatory proteins. These functions are collectively performed by molecular chaperones and proteases. This project will define the molecular basis of substrate selectivity for ATP-dependent proteases and determine the relationship between chaperones and proteases. A major focus will be directed towards the mechanistic analysis of novel AAA+ cofactors such as ClpS, which we recently discovered. A detailed analysis of such proteins is central to understanding how chaperones and protease (a) recognize their substrates and (b) compete for different substrates in vivo.Read moreRead less
Structural studies on the mitochondrial protein import machinery. Proteins transported across biological membranes are generally synthesized as precursors with signal sequences. These signal sequences are decoded by one of a number of membrane-specific protein transport machinery, but how this decoding occurs is largely unknown. This proposal aims to understand the structural basis of protein import into the mitochondrion, a poorly understood biological process. This study will enhance signif ....Structural studies on the mitochondrial protein import machinery. Proteins transported across biological membranes are generally synthesized as precursors with signal sequences. These signal sequences are decoded by one of a number of membrane-specific protein transport machinery, but how this decoding occurs is largely unknown. This proposal aims to understand the structural basis of protein import into the mitochondrion, a poorly understood biological process. This study will enhance significantly our understanding of mitochondrial biology, and will also have ramifications for other areas of protein transport.Read moreRead less
Regulation of the actin cytoskeleton by LIM kinase 2. Because the regulation of actin cytoskeleton is essential for many cellular processes including cell motility and the normal function of neurons, it is of great importance to understand its regulation. Elucidation of the molecular and biological mechanisms underlying the actin cytoskeleton including cell motility may enable the identification of novel therapeutic targets for the treatment of diseases such as cancer metastasis, Alzheimer disea ....Regulation of the actin cytoskeleton by LIM kinase 2. Because the regulation of actin cytoskeleton is essential for many cellular processes including cell motility and the normal function of neurons, it is of great importance to understand its regulation. Elucidation of the molecular and biological mechanisms underlying the actin cytoskeleton including cell motility may enable the identification of novel therapeutic targets for the treatment of diseases such as cancer metastasis, Alzheimer disease (AD) and/or Multiple Sclerosis (MS) in which the regulation of the actin cytoskeleton is affected.
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Analysis of the Role of Snapin in the Regulation of SNARE Complex Assembly. The aims of the proposed studies are to investigate the role played by a protein, snapin in the trafficking of membranes and cargo proteins between different compartments inside mammalian cells. Membrane trafficking is a fundamental cellular process that requires a family of related molecules termed SNARES. We have recently discovered that snapin interacts with certain members of the SNARE family, implying a critical rol ....Analysis of the Role of Snapin in the Regulation of SNARE Complex Assembly. The aims of the proposed studies are to investigate the role played by a protein, snapin in the trafficking of membranes and cargo proteins between different compartments inside mammalian cells. Membrane trafficking is a fundamental cellular process that requires a family of related molecules termed SNARES. We have recently discovered that snapin interacts with certain members of the SNARE family, implying a critical role in membrane trafficking. The proposed studies will provide important new insights into the molecular mechanisms underlying the function of both snapin and SNAREs, and membrane trafficking in general.Read moreRead less
Defining the pathways for the import of proteins into mitochondria. This application deals with the targeting of preproteins from the cytosol to the mitochondria in mammalian cells. The aims are to identify and characterise mitochondrial targeting signals within preproteins lacking typical N-terminal signal sequences; to characterise the roles of the cytosolic molecular chaperones such as Hsp90 and Hsp70 in assisting the movement of preproteins to the mitochondrial surface; to determine the inte ....Defining the pathways for the import of proteins into mitochondria. This application deals with the targeting of preproteins from the cytosol to the mitochondria in mammalian cells. The aims are to identify and characterise mitochondrial targeting signals within preproteins lacking typical N-terminal signal sequences; to characterise the roles of the cytosolic molecular chaperones such as Hsp90 and Hsp70 in assisting the movement of preproteins to the mitochondrial surface; to determine the interactions of both preproteins and cytosolic factors with outer membrane components and; to analyse the roles of individual TOM receptors in import. The results obtained will facilitate our understanding of general protein import processes and those specific for mammals.Read moreRead less
A Cytosolic Complex for Targeting Mitochondrial Proteins. Mitochondria are essential for the viability of cells, and are the major source of cellular energy via oxidative phosphorylation. A loss of mitochondrial function with age contributes to the ageing process and therefore understanding the basic functions of this organelle is an important aim in biology. In mammalian cells this organelle comprises about 1500 different proteins, 99% of which need to be imported from outside the organelle. ....A Cytosolic Complex for Targeting Mitochondrial Proteins. Mitochondria are essential for the viability of cells, and are the major source of cellular energy via oxidative phosphorylation. A loss of mitochondrial function with age contributes to the ageing process and therefore understanding the basic functions of this organelle is an important aim in biology. In mammalian cells this organelle comprises about 1500 different proteins, 99% of which need to be imported from outside the organelle. We have found that this requires a large protein complex to target the preproteins to the organelle. This research is directed to determining the component parts of this complex and the roles each component plays in the targeting process and in mitochondrial reproduction.Read moreRead less
Molecular Basis for the Mitochondrial Stress Response. The biogenesis of mitochondria depends on the co-ordinated expression of mitochondrial and nuclear genomes. Little is known about the extent and how the expression of both cellular genomes is co-ordinated. We have discovered a novel biological process, the mitochondrial stress response, whereby the establishment of stress within the mitochondria results in the upregulation of a suite of genes in the nucleus encoding proteins which rescue m ....Molecular Basis for the Mitochondrial Stress Response. The biogenesis of mitochondria depends on the co-ordinated expression of mitochondrial and nuclear genomes. Little is known about the extent and how the expression of both cellular genomes is co-ordinated. We have discovered a novel biological process, the mitochondrial stress response, whereby the establishment of stress within the mitochondria results in the upregulation of a suite of genes in the nucleus encoding proteins which rescue mitochondria from damage caused by stress. This project is to determine how stress is sensed in the mitochondrion and communicated to the nucleus resulting in alterations in gene expression. The project also aims to define the physiological role of mitochondrial chaperones in protein folding in the organelle.Read moreRead less
Regulation of Mitochondrial Biogenesis. This project brings together two disciplines, biochemistry and computer science, that have a great potential synergy in the nascent field of bioinformatics. It will provide an excellent training ground for research students who will develop a set of unique and valuable skills. It will also provide information on the process of ageing as this process is associated with a loss in bioenergetic function and other conditions such as diabetes, obesity and cardio ....Regulation of Mitochondrial Biogenesis. This project brings together two disciplines, biochemistry and computer science, that have a great potential synergy in the nascent field of bioinformatics. It will provide an excellent training ground for research students who will develop a set of unique and valuable skills. It will also provide information on the process of ageing as this process is associated with a loss in bioenergetic function and other conditions such as diabetes, obesity and cardiovascular disease in which mitochondrial oxidative metabolism is implicated.Read moreRead less
Transporting proteins to and within mitochondria. Mitochondria are found in all of our cells and are essential for life. They act like a nuclear power plant, providing the bulk of energy - but they can also kill the cell if the mitochondrial wall (membrane) is opened. Mitochondria contain about 1000 different proteins to function properly but almost all of them are made outside the compartment and must squeeze in through narrow membrane channels. This project will provide new insights into how p ....Transporting proteins to and within mitochondria. Mitochondria are found in all of our cells and are essential for life. They act like a nuclear power plant, providing the bulk of energy - but they can also kill the cell if the mitochondrial wall (membrane) is opened. Mitochondria contain about 1000 different proteins to function properly but almost all of them are made outside the compartment and must squeeze in through narrow membrane channels. This project will provide new insights into how proteins get into mitochondria and what factors help in this process. Besides providing new information about a process that is essential for life, the project will train students in molecular cellular biology techniques and will help foster strong international collaborations.Read moreRead less