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
All in the family: understanding a new class of bacterial toxins. This project aims to unravel missing molecular details of how a major superfamily of proteins is able to drill holes in cell membranes. Animals, plants, fungi and bacteria all use pore-forming proteins as cell-killing weapons of mass destruction. Despite their lethal nature and their roles in infection and immunity, how these proteins work remains enigmatic. The outcomes could reveal novel mechanisms general to these proteins and ....All in the family: understanding a new class of bacterial toxins. This project aims to unravel missing molecular details of how a major superfamily of proteins is able to drill holes in cell membranes. Animals, plants, fungi and bacteria all use pore-forming proteins as cell-killing weapons of mass destruction. Despite their lethal nature and their roles in infection and immunity, how these proteins work remains enigmatic. The outcomes could reveal novel mechanisms general to these proteins and provide fundamental insights in understanding vital physiological processes across all kingdoms of life. Ultimately, this knowledge may guide the design of artificial protein pores that are selective for specific molecules with applications such as measuring metal ions, sugars, pesticides or pollutants. Read moreRead less
The structural basis for MPEG1 mediated assembly of immune complexes. Macrophage Expressed Gene-1 (MPEG1) is an ancient pore forming perforin-like immune effector that is found throughout multicellular life. In humans MPEG1 is found in Macrophages (a type of immune cell) and functions to eliminate a wide range of different infectious microbes. In this study we will study how different modifications and molecular interactions drive MPEG1 function. Crucially our work will provide a framework to ....The structural basis for MPEG1 mediated assembly of immune complexes. Macrophage Expressed Gene-1 (MPEG1) is an ancient pore forming perforin-like immune effector that is found throughout multicellular life. In humans MPEG1 is found in Macrophages (a type of immune cell) and functions to eliminate a wide range of different infectious microbes. In this study we will study how different modifications and molecular interactions drive MPEG1 function. Crucially our work will provide a framework to understand how MPEG1 interacts with the interferon signalling pathway. These data will provide fundamental insight into how perforin-like proteins are controlled and will broadly inform new approaches to modify immune function and molecular signalling events.Read moreRead less
Understanding how pore-forming proteins punch holes in membranes. This project aims to unravel missing molecular details of how a major superfamily of proteins is able to drill holes in cell membranes. Animals, plants, fungi and bacteria all use pore-forming proteins as cell-killing weapons of mass destruction. Despite their lethal nature and their roles in infection and immunity, how these proteins work remains enigmatic. Project outcomes could reveal novel mechanisms general to these essential ....Understanding how pore-forming proteins punch holes in membranes. This project aims to unravel missing molecular details of how a major superfamily of proteins is able to drill holes in cell membranes. Animals, plants, fungi and bacteria all use pore-forming proteins as cell-killing weapons of mass destruction. Despite their lethal nature and their roles in infection and immunity, how these proteins work remains enigmatic. Project outcomes could reveal novel mechanisms general to these essential proteins and provide fundamental insights in understanding vital physiological processes across all kingdoms of life. Ultimately, the knowledge gained may prove useful in the engineering of membrane pores as highly specific sensors for a variety of molecules with nanotechnology and biotechnology applications.Read moreRead less
Pore-forming toxins: more than one way to make a hole. Animals, plants, fungi and bacteria all use pore-forming proteins as cell-killing weapons of mass destruction. Despite their lethal nature and their roles in infection and immunity, how these proteins work remains enigmatic. This project aims to unravel missing molecular details of how a major superfamily of such proteins is able to drill holes in cell membranes. The outcomes could reveal novel mechanisms general to these proteins and provid ....Pore-forming toxins: more than one way to make a hole. Animals, plants, fungi and bacteria all use pore-forming proteins as cell-killing weapons of mass destruction. Despite their lethal nature and their roles in infection and immunity, how these proteins work remains enigmatic. This project aims to unravel missing molecular details of how a major superfamily of such proteins is able to drill holes in cell membranes. The outcomes could reveal novel mechanisms general to these proteins and provide fundamental insights in understanding vital physiological processes across all kingdoms of life. Ultimately, this knowledge may guide the design of artificial protein pores that are selective for specific molecules with applications such as measuring metal ions, sugars, pesticides or pollutants.
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The structural basis for defensin-mediated membrane attack. This project aims to define how the innate defense proteins called defensins attack target membranes to cause cells to burst and die. It is often said that attack is the best form of defense, and the immune systems of plants and animals will often target the cell membranes of microbes and other pathogens to defend themselves. This project will identify the precise molecular mechanism underlying defensin activity, and clarify how ligand ....The structural basis for defensin-mediated membrane attack. This project aims to define how the innate defense proteins called defensins attack target membranes to cause cells to burst and die. It is often said that attack is the best form of defense, and the immune systems of plants and animals will often target the cell membranes of microbes and other pathogens to defend themselves. This project will identify the precise molecular mechanism underlying defensin activity, and clarify how ligand recognition and subsequent multimerisation leads to target membrane lysis. The project will establish the fundamental mechanisms regulating antimicrobial defense systems based on small proteins, and define a conceptual framework for the action of defensins to develop strategies to combat fungal infections.Read moreRead less
How do signals cross the cell membrane: the betacommon receptor family. This project aims to unravel missing molecular details of how a family of proteins, called the betacommon receptors, is able to signal across cell walls. This project aims to generate new knowledge about how membrane-bound receptors transmit biological signals in living organisms. Despite their fundamental importance in biology, how these proteins work remain enigmatic. Expected outcomes include discovery of novel mechanisms ....How do signals cross the cell membrane: the betacommon receptor family. This project aims to unravel missing molecular details of how a family of proteins, called the betacommon receptors, is able to signal across cell walls. This project aims to generate new knowledge about how membrane-bound receptors transmit biological signals in living organisms. Despite their fundamental importance in biology, how these proteins work remain enigmatic. Expected outcomes include discovery of novel mechanisms general to these types of protein receptors and fundamental insights in understanding vital physiological processes across all kingdoms of life. Ultimately, this new knowledge should benefit efforts to discover novel treatments in cases where malfunctioning receptors cause diseases in animals and humans.Read moreRead less
The mechanism of pore formation by Membrane Attack Complex/Perforin-like proteins. Members of the Membrane Attack Complex / Perforin (MACPF) family of proteins are essential for life, playing fundamental roles in immunity, tissue development and neuron formation. This project seeks to understand the basic mechanism of how MACPF proteins can form pores in target cells, a process central for killing in mammalian immunity.
A structural investigation into T cell signalling machines. The project aims to understand how receptor recognition events cause intracellular signalling.Membrane-bound receptors, their cognate ligands and the ensuing intracellular activation signal determine cellular fate. The project will explore events central to cellular immunity by examining the T cell signalling machinery. This project will use labelling, crystallographic and cryo-electron microscopy studies, to determine the molecular arc ....A structural investigation into T cell signalling machines. The project aims to understand how receptor recognition events cause intracellular signalling.Membrane-bound receptors, their cognate ligands and the ensuing intracellular activation signal determine cellular fate. The project will explore events central to cellular immunity by examining the T cell signalling machinery. This project will use labelling, crystallographic and cryo-electron microscopy studies, to determine the molecular architecture of the T cell receptor (TCR) CD3 complex, a molecular machine central to T cell signalling. This project should reveal how antigen recognition leads to T cell signal transduction which will create jobs, bring substantial health benefits and improve quality of life for Australians.Read moreRead less
A structural and molecular investigation into the basic mechanism of T cell receptor complex function. Cellular fate is determined by interactions between membrane-bound receptors and their cognate ligands. The basic mechanism of how such receptor-mediated recognition events cause intracellular signalling is poorly understood in most biological systems, including the cellular immune recognition axis. This project will explore events central to cellular immunity by examining the interactions cent ....A structural and molecular investigation into the basic mechanism of T cell receptor complex function. Cellular fate is determined by interactions between membrane-bound receptors and their cognate ligands. The basic mechanism of how such receptor-mediated recognition events cause intracellular signalling is poorly understood in most biological systems, including the cellular immune recognition axis. This project will explore events central to cellular immunity by examining the interactions centred on T-cell receptor complexes. This project will explore the molecular mechanisms underpinning these key receptor-recognition events and relate these observations to T-cell activation. The proposal will shed fundamental insight into Major Histocompatibility Complex restriction, T-cell development and how antigen recognition leads to T-cell signal transduction. Read moreRead less