Translocase Of The Outer Mitochondrial Membrane: X-ray Structure Determination Of Core Components
Funder
National Health and Medical Research Council
Funding Amount
$336,118.00
Summary
This research will address the issue of protein transport into mitochondria, cellular organelles bounded by a complex double-membrane system that are primarily responsible for servicing the energy requirements of actively respiring cells. The outer membrane, or envelope, surrounding each mitrochondrion, is separated from a second (or inner) membrane by an inter-membrane space. The translocase of the outer mitochondrial membrane (TOM) cooperates with the translocase of the inner mitochondrial mem ....This research will address the issue of protein transport into mitochondria, cellular organelles bounded by a complex double-membrane system that are primarily responsible for servicing the energy requirements of actively respiring cells. The outer membrane, or envelope, surrounding each mitrochondrion, is separated from a second (or inner) membrane by an inter-membrane space. The translocase of the outer mitochondrial membrane (TOM) cooperates with the translocase of the inner mitochondrial membrane (TIM) to mediate the passage of unfolded preproteins into the mitochondria. Proteins are usually bulky in their active folded state, so preproteins transit the membrane as extended polypeptide chains, as the channel through which they pass is relatively narrow. Ancillary praoteins aid in recognition and targeting of preproteins, and help to maintain them in an unfolded state prior to their translocation through the pore, and later ensure that they are able to fold into the correct conformation once they have arrived in the mitochondria. Our research will entail determination of the three-dimensional atomic-level structures of selected constituents of the TOM machinery, allowing us to visualise freeze-frame snapshots of some aspects of protein translocation in molecular details. In combination with recent biochemical data, this information will provide an architectural framework which we can use to help in our interpretation of complicated structure-function relationships between components of TOM and other proteins with which they integrate their activities during translocation events. Ultimately such fundamental research will lead to the development of strategies for dealing with disorders linked to mitochondrial defects in humans, including, amongst others, Parkinson's and Alzheimer's diseases.Read moreRead less
Mechanism Of Action Of Sec1p-like Proteins In Membrane Trafficking
Funder
National Health and Medical Research Council
Funding Amount
$234,936.00
Summary
One of the most important evolutionary changes that has occurred is the development of intracellular compartments. All eukaryotic cells possess numerous membrane-encased structures which provide the basis for intracellular specialisation. For example, in order to degrade unwanted components cells have developed degradative enzymes. It is vital for the cell that these enzymes are sequestered away from other cellular components to avoid destruction of valuable molecules. In addition, the cell has ....One of the most important evolutionary changes that has occurred is the development of intracellular compartments. All eukaryotic cells possess numerous membrane-encased structures which provide the basis for intracellular specialisation. For example, in order to degrade unwanted components cells have developed degradative enzymes. It is vital for the cell that these enzymes are sequestered away from other cellular components to avoid destruction of valuable molecules. In addition, the cell has developed a complex assembly line of modifications that are added to proteins in a specific order as they travel to their final destination within the cell. This necessitates the accurate passage of molecules between compartments, a process known as vesicle transport. To orchestrate the complex network of vesicular transport steps between all of the various intracellular compartments it is necessary to employ complex machinery to guide and check that these steps occur with high fidelity. The goal of our research proposal is to define the function of one of the molecules involved in this control process, the so-called Sec1p proteins. The strength of our proposal lies in the diversity of our approach. We intend to explore the molecular advantages of a relatively simple eukaryotic organism, a yeast cell, and apply the findings obtained from this cell to a more complex but highly related vesicular transport process; that of the insulin-regulated movement of a glucose transporter in mammalian fat and muscle cells. While we intend to apply our findings to the treatment of patients with diabetes, it is our ultimate goal to be able to learn more about this fundamental cell biological process so that we can apply our knowledge to understanding many different disease states.Read moreRead less
Mechanism Of Action Of Sec1p-like Proteins In Membrane Trafficking.
Funder
National Health and Medical Research Council
Funding Amount
$440,250.00
Summary
One of the most important evolutionary changes that has occurred is the development of intracellular compartments. All eukaryotic cells possess numerous membrane-encased structures which provide the basis for intracellular specialisation. For example, in order to degrade unwanted components cells have developed degradative enzymes. It is vital for the cell that these enzymes are sequestered away from other cellular components to avoid destruction of valuable molecules. In addition, the cell has ....One of the most important evolutionary changes that has occurred is the development of intracellular compartments. All eukaryotic cells possess numerous membrane-encased structures which provide the basis for intracellular specialisation. For example, in order to degrade unwanted components cells have developed degradative enzymes. It is vital for the cell that these enzymes are sequestered away from other cellular components to avoid destruction of valuable molecules. In addition, the cell has developed a complex assembly line of modifications that are added to proteins in a specific order as they travel to their final destination within the cell. This necessitates the accurate passage of molecules between compartments, a process known as vesicle transport. To orchestrate the complex network of vesicular transport steps between all of the various intracellular compartments it is necessary to employ complex machinery to guide and check that these steps occur with high fidelity. The goal of our research proposal is to define the function of one of the molecules involved in this control process, the so-called Sec1p proteins. The strength of our proposal lies in the diversity of our approach. We intend to explore the molecular advantages of a relatively simple eukaryotic organism, a yeast cell, and apply the findings obtained from this cell to a more complex but highly related vesicular transport process; that of the insulin-regulated movement of a glucose transporter in mammalian fat and muscle cells. While we intend to apply our findings to the treatment of patients with diabetes, it is our ultimate goal to be able to learn more about this fundamental cell biological process so that we can apply our knowledge to understanding many different disease states.Read moreRead less