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Trevor Lithgow

Molecular cell biology
Our lab works on protein targeting; how proteins are sent to their correct sub-cellular location. This fundamental process is the basis of how cells build their intracellular membranes, and how pathogenic microbes target their hosts with toxic proteins. Ten to twenty per cent of the proteins expressed in a given eukaryote cell are targeted to mitochondria, as are many of the effector proteins made by pathogenic bacteria. The eukaryotic transport pathways that take proteins to mitochondria are driven by a set of molecular machines called the TOM and SAM complexes. Bacteria also have a version of the SAM complex in their outer membranes.

The outer membranes of bacteria and mitochondria are assembled by a conserved mechanism. (A) Arrows indicated the directional flow of protein substrates from their site of synthesis either the Omp85.protein in the outer membrane of bacteria, or the Sam50 protein in the outer membrane of mitochondria. (B) Detailed sequence analysis and phylogenetics established Sam50 as a member of the Omp85 family of proteins, being composed of a series of POTRA domains and the characteristic “surface antigen domain” (Dolezal et al 2006 "Evolution of the molecular machines for protein import into mitochondria" Science 313, 314-318) Abstract Full text of Science paper
Our current research is aimed at characterizing the function of protein transport machines in mitochondria and bacteria, using knowledge of the mitochondrial system and expertise in genetics, biochemistry and cell biology to understand how bacterial pathogens assemble protein transport machines in their outer membranes, and how these machines transport “effector” proteins into human cells.

Omp85-type beta-barrels function as Type V secretion systems. Autotransporters, such as VacA from Helicobacter pylori, have a an effector protein substrate synthesized as part of the Omp85-type beta-barrel, whereas in two-partner type secretion systems such as the ZirT/ZirS system of Salmonella, the barrel (ZirT) and effector protein (ZirS) are made and targeted as distinct polypeptides. While not strictly conforming to the “surface antigen domain”, the beta-barrel translocators of all of these transport systems are related.
Current projects
The use of hidden Markov models and other bioinformatic approaches with Vladimir Likic is aiding our understanding of the relationships between mitochondrial and bacterial membrane assembly pathways. With Tony Purcell, we are using mass spectrometry to identify new components of these pathways. In collaboration with Dick Strugnell, Roy Robins-Browne, Ben Adler and Julian Rood, we have initiated projects on the assembly and function of bacterial protein secretion machines. The projects employ a broad range of techniques in cell biology, genetics, computer science and molecular biology. New projects include: Defining step-by-step how integral membrane proteins are assembled into the mitochondrial outer membrane. Good evidence suggests a conserved mechanism is behind the assembly of tail-anchorder proteins such as the Bcl-2 family and beta-barrels, and the structural and energetic demands of each process need to be defined Detailing how and when bacterial secretion systems are assembled into outer membranes. These machines are essential for the secretion of the effector proteins bacteria use for infection and transmission Understanding the targeting of bacterial effector proteins to mitochondria. In order to prevent host cell death, many bacterial effector proteins appear to dampen signals that would emanate from mitochondria. Understanding how these proteins reach the mitochondria and how they function there is critical to unraveling host-pathogen responses
Yeast as a model organism
The baker's yeast Saccharomyces cerevisiae has been used as a model by geneticists and cell biologists for many years. The complete sequence of the yeast genome and information about the proteins it encodes can be found at the Stanford University Saccharomyces Genome Database. Yeast cells have proven to be a reliable model for the way the cells of plants and animals, including humans, function.
Trevor's other links of interest
Trevor's complete list of publications

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