Investigating the dynamic nature of antibody stability. The aim of the project is to provide insights into the molecular mechanisms of antibody stability. Monoclonal antibodies have transformed the study of biological processes and represent blockbuster therapeutics for cancer and inflammation. Unfortunately, antibodies often display limited stability, which greatly hinders development. Mutations have recently been identified that render human antibodies resistant to aggregation, and high-resolu ....Investigating the dynamic nature of antibody stability. The aim of the project is to provide insights into the molecular mechanisms of antibody stability. Monoclonal antibodies have transformed the study of biological processes and represent blockbuster therapeutics for cancer and inflammation. Unfortunately, antibodies often display limited stability, which greatly hinders development. Mutations have recently been identified that render human antibodies resistant to aggregation, and high-resolution crystal structures are being used to identify function. Intriguingly, preliminary data indicates that the mutations do not affect the native antibody structure, but rather influence dynamic states. The project plans to use a combination of mutagenesis, molecular dynamics simulation and deuterium exchange to study antibody dynamics.Read moreRead less
Imaging the T cell signalling machinery . The conversion of external stimuli to the interior of a cell is a fundamental process that underpins many unique facets of biology, including cellular movement, nerve transmission, response to hormones and immune recognition. However, the basic mechanism by which such signals are transmitted across cellular membranes is poorly understood. This proposal will seek to bridge this gap in our knowledge by imaging a multi-component “decision-making” machine th ....Imaging the T cell signalling machinery . The conversion of external stimuli to the interior of a cell is a fundamental process that underpins many unique facets of biology, including cellular movement, nerve transmission, response to hormones and immune recognition. However, the basic mechanism by which such signals are transmitted across cellular membranes is poorly understood. This proposal will seek to bridge this gap in our knowledge by imaging a multi-component “decision-making” machine that controls whether or not the immune system becomes activated. Accordingly, this proposal will provide far-reaching insights into molecular events that are of central importance to the initiation of immunity, and thus will ultimately benefit society via improvements in health.Read moreRead less
Molecular mechanisms of novel bacterial copper defense proteins. This project aims to reveal molecular and cellular mechanisms used by bacteria to neutralise the destructive effects of copper. Copper is an essential trace element in living systems. It is toxic to bacteria and so plays a vital role in nutritional immunity. To counteract copper toxicity, bacteria have evolved defense mechanisms. The project will investigate a novel but poorly understood class of bacterial proteins, the suppressor ....Molecular mechanisms of novel bacterial copper defense proteins. This project aims to reveal molecular and cellular mechanisms used by bacteria to neutralise the destructive effects of copper. Copper is an essential trace element in living systems. It is toxic to bacteria and so plays a vital role in nutritional immunity. To counteract copper toxicity, bacteria have evolved defense mechanisms. The project will investigate a novel but poorly understood class of bacterial proteins, the suppressor of copper sensitivity proteins, that contribute to this key virulence trait. The expected outcomes will be fundamental new knowledge of metallo-protein diversity, bacterial virulence mechanisms, and membrane protein function with potential impact on health, environment, and biotechnology.Read moreRead less
The structure of heteromeric amyloid fibrils with signaling activity. This project aims to determine the composition, structure and properties of important protein complexes involved in a newly identified cell death pathway known as necroptosis. This cell death pathway removes unwanted or damaged cells during development or infection. These necroptosis protein complexes are unusual because they have a fibrillar amyloid structure, contain more than one protein type in the fibrils and have a funct ....The structure of heteromeric amyloid fibrils with signaling activity. This project aims to determine the composition, structure and properties of important protein complexes involved in a newly identified cell death pathway known as necroptosis. This cell death pathway removes unwanted or damaged cells during development or infection. These necroptosis protein complexes are unusual because they have a fibrillar amyloid structure, contain more than one protein type in the fibrils and have a functional, signalling role. The research will determine how these fibrils form and how the structures confers biological function. It could identify features in these fibrils that can be targeted as a means of ultimately preventing tissue damage after heart attack and stroke.Read moreRead less
Molecular mechanisms for copper trafficking across membranes. Copper is a trace metal that is essential for all forms of life, however it is toxic in excess. Tightly controlled protein-based metalloregulatory systems are responsible for copper uptake and homeostasis in all cells. Components of these systems are integral membrane transport proteins, which include the Ctr proteins that are solely responsible for copper uptake into eukaryotic cells. This project aims to define the molecular mechani ....Molecular mechanisms for copper trafficking across membranes. Copper is a trace metal that is essential for all forms of life, however it is toxic in excess. Tightly controlled protein-based metalloregulatory systems are responsible for copper uptake and homeostasis in all cells. Components of these systems are integral membrane transport proteins, which include the Ctr proteins that are solely responsible for copper uptake into eukaryotic cells. This project aims to define the molecular mechanisms by which the Ctr proteins transport copper across eukaryotic cell membranes, by solving their three-dimensional structures by X-ray crystallography.Read moreRead less
Biologically inert probes to unravel nutrient directed cellular processing . In this project we will develop novel compounds that can act as probes of the pathways present in cells for the uptake of nutrients and other essential molecules and show how to generate new agents for identifying and targeting specific populations of cells. The project will generate new tools for understanding biological processes including cell transport and processing. The insights gained from this work are expected ....Biologically inert probes to unravel nutrient directed cellular processing . In this project we will develop novel compounds that can act as probes of the pathways present in cells for the uptake of nutrients and other essential molecules and show how to generate new agents for identifying and targeting specific populations of cells. The project will generate new tools for understanding biological processes including cell transport and processing. The insights gained from this work are expected to help guide the development of new agents for selectively delivering imaging and biologically active agents to cells.Read moreRead less
In depth characterisation of the gamma delta T cell immune synapse. This project aims to comprehensively characterise the activation principles of gamma delta T cells. These cells have an understudied but central role in vertebrate immunity and development. A missing piece of the puzzle is how gamma delta T cells sense stress and how this signal leads to activation. Expected outcomes include the generation of fundamental knowledge in immunology and structural biology. This proposal uses high-ski ....In depth characterisation of the gamma delta T cell immune synapse. This project aims to comprehensively characterise the activation principles of gamma delta T cells. These cells have an understudied but central role in vertebrate immunity and development. A missing piece of the puzzle is how gamma delta T cells sense stress and how this signal leads to activation. Expected outcomes include the generation of fundamental knowledge in immunology and structural biology. This proposal uses high-skilled techniques, including cryo-electron microscopy and single-molecule imaging and holds ancillary benefits to postgraduate students. Anticipated outcomes include influential publications, building a critical mass of expertise in Australia and fostering international collaborations with Australia at the epicentre.Read moreRead less
Lifespan-dependent molecular shaping of the T cell receptor repertoire. Mammals have an intricate and highly complex immune system, whose function alters throughout life. Why and how this occurs is very unclear however, yet remains a crucial question. This project aims to provide fundamental knowledge on how the human lifespan shapes specific T cell receptors and determine molecular mechanisms underlying gain-of-function and loss-of-function during immunologically distinct phases of life. This p ....Lifespan-dependent molecular shaping of the T cell receptor repertoire. Mammals have an intricate and highly complex immune system, whose function alters throughout life. Why and how this occurs is very unclear however, yet remains a crucial question. This project aims to provide fundamental knowledge on how the human lifespan shapes specific T cell receptors and determine molecular mechanisms underlying gain-of-function and loss-of-function during immunologically distinct phases of life. This project will provide analysis of multi-dimensional, high throughput datasets to identify fundamental links between the transcriptional landscape and TCR signatures across human lifespan, thus will significantly answer key immunological questions in the field.Read moreRead less
Uncovering the molecular mechanisms of potassium channel activity. The aim of this project is to determine the mechanisms of protein-mediated potassium ion transport across cell membranes. It will combine advanced simulations, structural biology and electrophysiology to describe the detailed molecular processes underscoring calcium-activated potassium channel conduction, gating and inactivation. The expected outcome is an improved description of how ion channels recognise and respond to physiolo ....Uncovering the molecular mechanisms of potassium channel activity. The aim of this project is to determine the mechanisms of protein-mediated potassium ion transport across cell membranes. It will combine advanced simulations, structural biology and electrophysiology to describe the detailed molecular processes underscoring calcium-activated potassium channel conduction, gating and inactivation. The expected outcome is an improved description of how ion channels recognise and respond to physiological stimuli to control electrical signalling the body. Our results will provide benefits in the form of basic understanding relevant to ion transport phenomena in biological systems, and atomic-level views of nervous system function to guide future directions in pharmacology.Read moreRead less
Multi-Scale Model-Based Simulation of Glass Fragmentation under Blast Loading. It is estimated that most injuries from bomb blasts can be attributed to airborne sharp glass fragments. The proposed project will help us gain better understanding of glass failure mechanism under impact/blast loading. The results from the proposed project are expected to help in developing more effective blast-resistant transparency, ensuring the reliability and quality of buildings and facilities, mitigating injury ....Multi-Scale Model-Based Simulation of Glass Fragmentation under Blast Loading. It is estimated that most injuries from bomb blasts can be attributed to airborne sharp glass fragments. The proposed project will help us gain better understanding of glass failure mechanism under impact/blast loading. The results from the proposed project are expected to help in developing more effective blast-resistant transparency, ensuring the reliability and quality of buildings and facilities, mitigating injury or death due to flying glass fragments, and eventually enhancing public safety and security.Read moreRead less