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
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
Methods for Protein Structure Analysis by Electron Paramagnetic Resonance. This highly interdisciplinary project aims to establish new tools to analyse the structure and motions of proteins that are otherwise difficult to study. A combination of advanced biochemistry, modern magnetic spectroscopy methods, and high-performance computing techniques will be applied to study proteins at physiological concentrations and in complex environments. New techniques will be developed and tested on proteins ....Methods for Protein Structure Analysis by Electron Paramagnetic Resonance. This highly interdisciplinary project aims to establish new tools to analyse the structure and motions of proteins that are otherwise difficult to study. A combination of advanced biochemistry, modern magnetic spectroscopy methods, and high-performance computing techniques will be applied to study proteins at physiological concentrations and in complex environments. New techniques will be developed and tested on proteins of high biochemical or biomedical importance, and the approach will be applied to established drug targets.Read moreRead less
Mastering pyrimidine editing in RNA. Many plants and animals can alter their genetic information via RNA (ribonucleic acid) editing, a process that is often essential for the growth and development of the organism. This ability provides accurate control over gene expression and has great potential as a biotechnological tool in agriculture and medicine. RNA editing could be used to switch genes on or off in biotechnological production systems with an unprecedented degree of precision, or to corre ....Mastering pyrimidine editing in RNA. Many plants and animals can alter their genetic information via RNA (ribonucleic acid) editing, a process that is often essential for the growth and development of the organism. This ability provides accurate control over gene expression and has great potential as a biotechnological tool in agriculture and medicine. RNA editing could be used to switch genes on or off in biotechnological production systems with an unprecedented degree of precision, or to correct genetic diseases. This project aims to understand two RNA editing pathways in plants, one of which is found nowhere else and likely to involve a novel enzymatic mechanism. We will use the understanding gained to develop novel RNA processing tools usable in any living organism.Read moreRead less
Uncovering mechanisms of protein multifunctionality. This project aims to use viral proteins to uncover fundamental mechanisms underlying protein multifunctionality, a central but poorly understood aspect of biology. This project expects to use multidisciplinary approaches to define novel and unexpected mechanisms by which single protein sequences can generate proteins with profoundly different structures and functions. Expected outcomes include a major shift in the understanding of protein fun ....Uncovering mechanisms of protein multifunctionality. This project aims to use viral proteins to uncover fundamental mechanisms underlying protein multifunctionality, a central but poorly understood aspect of biology. This project expects to use multidisciplinary approaches to define novel and unexpected mechanisms by which single protein sequences can generate proteins with profoundly different structures and functions. Expected outcomes include a major shift in the understanding of protein function in life, with most immediate impact in virology. This should provide significant benefits in identifying new strategies for treating viral infections, but also enhance developing multidisciplinary approaches to solve complex biological problems.Read moreRead less
The viral fusosome: a modular machinery for cargo delivery to target cells. The delivery of proteins, RNA and DNA into cells is a critical process in normal cellular biology, virus infection and biotechnology applications such as gene editing. Enveloped viruses achieve this maneuver with exquisite efficiency and specificity using a complex machinery mediating their fusion with cellular membranes for stealth genome delivery. Remarkably, all characterised viral fusion proteins belong to only 3 cla ....The viral fusosome: a modular machinery for cargo delivery to target cells. The delivery of proteins, RNA and DNA into cells is a critical process in normal cellular biology, virus infection and biotechnology applications such as gene editing. Enveloped viruses achieve this maneuver with exquisite efficiency and specificity using a complex machinery mediating their fusion with cellular membranes for stealth genome delivery. Remarkably, all characterised viral fusion proteins belong to only 3 classes defined >16 years ago and sharing surprisingly conserved mechanisms. We identified a novel class of fusion proteins with unique architecture in ubiquitous insect viruses. The Project will elucidate the structural and functional hallmarks of this fusion machinery providing a platform for its engineering.Read moreRead less
Engineering self-assembled intracellular biological condensates. Cells depend on proteins linking together to build cellular structure, but how weak interactions build stable structure is a mystery. New evidence suggests proteins come together and then change state, employing liquid-like behaviour that builds vital nanoscale structure, such as nuclear bodies called paraspeckles. This project will unlock the secrets of this mysterious behavior of proteins, using paraspeckles as a model. We will u ....Engineering self-assembled intracellular biological condensates. Cells depend on proteins linking together to build cellular structure, but how weak interactions build stable structure is a mystery. New evidence suggests proteins come together and then change state, employing liquid-like behaviour that builds vital nanoscale structure, such as nuclear bodies called paraspeckles. This project will unlock the secrets of this mysterious behavior of proteins, using paraspeckles as a model. We will use this information for nanotechnology application to build a synthetic paraspeckle inspired structure with bespoke function. Benefits will include new concepts in how vital cell structure is assembled and disassembled, and nanotechnology and synthetic biology tools to manipulate cellular processes.Read moreRead less