The Landsberg Lab
Structural Biology of Macromolcelular Machines and Disease
Our Research
Virulence factors in pathogenic bacteria: Repurposing Nature's weapons for good
Bacteria are present in vast numbers in all but the rarest of environments, and so face a constant battle for resources. They therefore possess a diverse and in many cases unique arsenal of molecular weaponry that allows them to acquire and protect nutrient sources essential to their survival.
ABC toxins are virulence factors - part of a bacterium's molecular weaponry - that were first identified in the "glowing" insecticidal bacteria, Photorhabdus luminescens. They are most commonly found in other insecticidal bacteria, but genes predicted to encoded closely related toxins have also been identified in human bacterial pathogens. We and other groups around the world are slowly deciphering how ABC toxins function as part of a bacterial organisms' arsenal at a molecular level. Using state-of-the-art techniques in single particle cryo-electron microscopy, together with other more historically-established techniques in structural biology, we were amongst the first people to gain a glimpse of how these toxins are assembled in complex molecular machines that deliver highly potent molecules to specifically targeted cells.
Part of our ongoing research is focused on understanding whether ABC toxins are highly specialised devices utilised by insectidal bacteria to kill insects, or whether the mechanism they employ might be more widespread in biology. So far it seems that ABC toxins might utilise this single intricate mechanism to deliver not only potent cyotoxic molecules (which kill targeted cells) but also antibiotics (which might prevent colonisation of an insect cadaver by competing micro-ogranisms) and potentially, a range of other bioactive proteins. Interestingly, different bacterial organisms produce ABC toxins that selectively target specific cells and/or cells from a specific host organism, and so we are also interested in learning more about how this discrimination occurs.
Funding
Marden Fund - Project Grant (2015-2017) "RHS-repeat-containing proteins, a new paradigm for targeted protein delivery." Lott, Hurst, Landsberg
Australian Research Council - Project Grant (2017-2019) "Unravelling the molecular mechanism of ABC toxins." Landsberg, Lott, Hurst.
Understanding how viruses are assembled and how they get in and out of host cells
Viruses are infectious microorganisms that rely on other living organisms to replicate. Enveloped viruses represent a major class of viruses that have as part of their structure an outer layer (a lipid envelope) that protects the inner structure of the virus particle (or virion). This envelope is not initially present when the virus forms, but rather is acquired from the native lipid membrane of an infected host cell, usually during release of the virus from the infected cell.
The point at which an enveloped virus acquires its membrane coat represents a key mechanistic step in enveloped virus infection. The host cell membrane is deformed into a budded structure, within which the pre-mature virus particle is ensheathed and eventually this particle pinches off the host membrane. For a significant subset of viruses that includes HIV and Ebola, this process is accomplished by hijacking a group of host cell proteins normally involved in protein trafficking. Known as ESCRT proteins, these usually organise the encapsulation of protein receptors within lipid-ensheathed compartments (vesicles), a process that allows protein receptors to be
directed to specific intracellular desintations. Conveniently for the virus, the budding of membrane-coated viruses from infected cells, and of cargo-containing vesicles from intracellular membranes are morphologically similar events, making these protein trafficking complexes perfectly suited to the job required by the virus. We are therefore trying to obtain a better understanding of this process in the hope that this may help us to define new strategies for the development of antiviral compounds.
Funding
National Health & Medical Research Council - Project Grant (2013-2016) "Endosomal protein trafficking complexes - therapeutic targets for novel antivirals." Landsberg
MAWA Trust - Research & Development Grant (2013) "Structure of a novel protein target for anti-viral drugs that is conserved between yeast and humans." Munn, Landsberg
The role of macromolecular machines in cancer and infectious diseases
We are also interested in learning more generally about how the function (or loss of function) associated with many other specific proteins leads to diseases. In particular we are interested in the role of protein-protein interactions in disease, since most of the proteins encoded by our genome rarely act in isolation but rather combine together with other proteins and/or biomolecules to trigger or regulate a particular biological outcome. Macromolecular machines are large assemblies built from many individual proteins that function collectively as a single, consolidated biological molecule. Since the most historically common methods for characterising protein structure (e.g. NMR, X-ray crystallography) tend to have low success rates when applied to large molecules with many discrete components, we instead predominantly use cryo-electron microscopy to investigate the structure of macromolecular machines at the nanoscale.
Our research in this area is of relevance to a wide range of diseases including various cancers, autoimmune diseases and neurodegenerative diseases, as well as diseases caused by other infectious viruses and bacteria.
Current Grants
Australian Research Council - LIEF Grant (2015) "Reaching new heights in high-resolution electron microscopy." Hankamer, Landsberg et al.
National Health & Medical Research Council - Project Grant (2017-2021) "Structure and function of a cancer-linked co-regulator complex." Mackay, Landsberg et al.
Funding Bodies
We are grateful to the following funding partners that support our work.
