Deciphering the cellular defences against aggregating proteins in human disease. Cells have inbuilt defences for coping with proteins that bend into abnormal sticky shapes that form toxic clusters. In many diseases, including Huntington's, the clusters severely damage nerve cells. This project will identify the genes and mechanisms cells use to protect themselves from toxic clusters, which could provide new therapeutic targets.
Discovery Early Career Researcher Award - Grant ID: DE150101243
Funder
Australian Research Council
Funding Amount
$371,000.00
Summary
The molecular mechanisms of dual nucleic acid specificities of SFPQ. Dynamic interactions between proteins and nucleic acids are a fundamental process in gene regulation, where aberrant regulation leads to lethality or various diseases. This project aims to elucidate the underlying mechanisms of DNA-RNA interplay with a multifunctional nuclear protein, splicing factor proline/glutamine-rich (SFPQ) in gene regulation at the molecular level by characterising the interactions between SFPQ and nucle ....The molecular mechanisms of dual nucleic acid specificities of SFPQ. Dynamic interactions between proteins and nucleic acids are a fundamental process in gene regulation, where aberrant regulation leads to lethality or various diseases. This project aims to elucidate the underlying mechanisms of DNA-RNA interplay with a multifunctional nuclear protein, splicing factor proline/glutamine-rich (SFPQ) in gene regulation at the molecular level by characterising the interactions between SFPQ and nucleic acids. The results will provide a fundamental understanding of the molecular mechanisms of dual nucleic acid specificities of nuclear proteins in gene regulation, for which no structural information is currently available.Read moreRead less
The early structural assembly of high-density lipoproteins. This project aims to study the interaction between proteins and lipids, a fundamental aspect of cellular processes in all organisms. Lipid binding by apoA-I forms high-density lipoproteins (HDL) in the bloodstream, which removes cholesterol from the body. This project will define the types of lipids that bind first to the apolipoprotein (apo) A-I and the structural mechanisms of this process. The conformation of lipid binding proteins o ....The early structural assembly of high-density lipoproteins. This project aims to study the interaction between proteins and lipids, a fundamental aspect of cellular processes in all organisms. Lipid binding by apoA-I forms high-density lipoproteins (HDL) in the bloodstream, which removes cholesterol from the body. This project will define the types of lipids that bind first to the apolipoprotein (apo) A-I and the structural mechanisms of this process. The conformation of lipid binding proteins often changes during lipid binding. However, the structural mechanisms and conformational rearrangements are poorly understood. This project expects to understand the function of HDL and the structural mechanisms of lipid binding proteins in general. The results will have far-reaching applications in biology, human health, and biotechnology, including food and biopharmaceutical processing.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE210100122
Funder
Australian Research Council
Funding Amount
$725,000.00
Summary
Hydrogen-deuterium exchange system - a missing link in protein analysis . Proteins are highly dynamic molecules that are essential to life. This project aims to acquire a fully automated and integrated hydrogen-deuterium exchange system, a powerful tool for analysing the motion of proteins and their interactions with other molecules. Expected outcomes include a new capability for biology labs around Australia by (1) increasing success rates of difficult projects that aim to visualise 3D protein ....Hydrogen-deuterium exchange system - a missing link in protein analysis . Proteins are highly dynamic molecules that are essential to life. This project aims to acquire a fully automated and integrated hydrogen-deuterium exchange system, a powerful tool for analysing the motion of proteins and their interactions with other molecules. Expected outcomes include a new capability for biology labs around Australia by (1) increasing success rates of difficult projects that aim to visualise 3D protein structures and (2) providing rapid information about protein interaction sites. Anticipated benefits include the generation of dynamic data that will be highly complementary to static pictures of protein structures. This will enable clever design of new proteins with beneficial uses in the biotechnology industry.Read moreRead less
Identification of Proteins that Regulate Apoptosis Through Interaction With IAPS. Apoptosis is the process by which multicellular organisms eliminate unwanted cells. Identifying proteins involved in cell death regulation is central to our understanding of disease states arising from aberrations in this process. The mammalian protein DIABLO, promotes cell death by interacting with and antagonising inhibitor of apoptosis proteins (IAPS). Given the existence of several IAP regulatory proteins (IRPs ....Identification of Proteins that Regulate Apoptosis Through Interaction With IAPS. Apoptosis is the process by which multicellular organisms eliminate unwanted cells. Identifying proteins involved in cell death regulation is central to our understanding of disease states arising from aberrations in this process. The mammalian protein DIABLO, promotes cell death by interacting with and antagonising inhibitor of apoptosis proteins (IAPS). Given the existence of several IAP regulatory proteins (IRPs) in insects, other mammalian IRPs probably also exist. These may be of equal importance in regulating apoptosis, especially in tissues where DIABLO is not expressed. The main aim of the proposed study is to idenitify and characterise other IRPs in mammalian cells.Read moreRead less
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
Imaging the action of antimicrobial peptides in living cells. The purpose of this project to use a special magnifying glass to watch molecules invading and killing cells. The outcome will be to identify the mechanism of cell killing to help in the future design of better antibiotics.
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
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE100100036
Funder
Australian Research Council
Funding Amount
$470,000.00
Summary
A protein molecular interaction and localization facility. This proposal will address a major gap in our mass spectrometry capabilities and aid in our understanding of protein interactions and tissue distribution in areas such as neuroscience, microbiology, immunology, and botany, as well as enhance our understanding of fundamental gas phase chemistry of protein molecules. It brings together a highly successful multidisciplinary team of high-profile researchers with a track record of collaborati ....A protein molecular interaction and localization facility. This proposal will address a major gap in our mass spectrometry capabilities and aid in our understanding of protein interactions and tissue distribution in areas such as neuroscience, microbiology, immunology, and botany, as well as enhance our understanding of fundamental gas phase chemistry of protein molecules. It brings together a highly successful multidisciplinary team of high-profile researchers with a track record of collaboration and delivering outcomes from shared facilities. In addition to these key scientific outcomes this project will also facilitate the training of several new personnel in a skill area for which there is a critical shortage (mass spectrometry) and promote true cross-disciplinary skills.Read moreRead less
Defining the cellular impacts of protein aggregation in neurodegenerative disease with an aggreomics platform. The brain disease Huntington’s is caused by abnormally shaped proteins that assemble into toxic clusters. This project will design new bioprobes to track how these clusters form and cause damage to cells. This strategy will also provide new opportunities for discovering novel therapeutic targets.