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
Targeting To Mitochondria Of Tail-Anchored Proteins. Defining The Molecular Apparatus Of Targeting.
Funder
National Health and Medical Research Council
Funding Amount
$254,751.00
Summary
The cells of the body have an intricate and dynamic internal architecture, with the components (proteins, lipids, and nucleic acids) of the cell carefully arranged. It is widely viewed that just how each component finds its place in the cell, the cellular adressing system, is of critical importance. This was recognized this year by the award of the Nobel Prize in Medicine to Dr. Gunter Blobel for his work on the signals that direct different proteins to their correct destination. One such destin ....The cells of the body have an intricate and dynamic internal architecture, with the components (proteins, lipids, and nucleic acids) of the cell carefully arranged. It is widely viewed that just how each component finds its place in the cell, the cellular adressing system, is of critical importance. This was recognized this year by the award of the Nobel Prize in Medicine to Dr. Gunter Blobel for his work on the signals that direct different proteins to their correct destination. One such destination is the mitochnondria, the particles in the cell that produce chemical energy. The work in this proposal is designed to define precisely the molecular apparatus that targets a group of proteins to mitochondria. This group, proteins that are inserted into the mitochondria at one end of the protein, includes a variety of critical proteins, including those that determine the life or death of a cell. We will define both the address contained within those proteins, and the machinery on the mitochondria that recognizes that address, and ensures that those proteins will become part of the mitochondria. This research has two applications. By understanding the address, we will be able to decode the vast amount genomic data that is being produced, to predict exactly which proteins are delivered to mitochondria. Secondly, by understanding the targeting machinery, we may begin to design molecules that can inhibit its function, and thus manipulate the delivery of those proteins that affect cell life and death.Read moreRead less
Remodelling Of Bacterial Outer Membranes: Implications For Vaccine Development.
Funder
National Health and Medical Research Council
Funding Amount
$558,189.00
Summary
We have identified proteins located in bacteria that are responsible for growth and the transport of essential nutrients. We will use a combination of bacterial genetics, protein biochemistry and immunological techniques to fully characterize these proteins. This strategic knowledge has direct implications for vaccine development and National security, since similar species of bacteria were amongst the first biological weapons.