The Bacterial Secretosome

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All cells are surrounded by membranes, made up from a double layer of fatty molecules called phospholipids. Cell membranes act as a molecular "skin", keeping the cell's insides in, and separating different biochemical reactions. The barrier needs to be breached in a controlled manner to allow transport of nutrients, waste products and for communication with the outside world; this is achieved by a wide range of membrane-inserted proteins. We understand a great deal about the diverse biological functions that membrane proteins bestow, such as transport, respiration, photosynthesis. However, we know very little about how membranes are formed, or about the necessary transport of proteins across or into membranes during their biogenesis.Our proposal aims to understand more about how the cell's protein secretion occurs. The secretory ('Sec' for short) machinery is essential for life - for every cell in every organism. The project concerns this process, in very simple bacterial cells. Bacteria secrete proteins for a wide range of membrane and extracellular activities including for: cell adherence, pathogenicity, the degradation of antibiotics, including also the biogenesis of the protective cell wall. A major class of bacteria known as Gram-negatives, possess a cell wall composed of a periplasm with a peptidoglycan (PG) layer, surrounded by an outer-membrane. The biogenesis of the cell wall is dependent on protein secretion through from the cell interior through the Sec machinery. Proteins of the periplasm can readily fold and remain there. Proteins are also transported across or into the outer membrane by another transport machine called the BAM complex, but it is not clear how they are shuttled there, to ensure the process is rapid and efficient.We have identified an interaction between the Sec machinery of the inner plasma membrane and the BAM complex, forming a structure that spans the entirety of the cell wall. This giant assembly, which we have called the bacterial 'secretosome', could form a contiguous conduit for very efficient passage of proteins from the cytosol to the outer-membrane. Its existence will have far reaching implications for our understanding of outer-membrane biogenesis.The project will harness complementary expertise in biochemistry and new breakthrough technologies in imaging by light and high-resolution electron cryo-microscopy. These scientific methods will illuminate the architecture of the secretosome, and how it works. The results of the project will be important because the bacterial cell wall, is vulnerable to attack. The weakening of the cell wall, or a compromise in its biogenesis or regenerative capabilities could be lethal. Therefore, new information towards our understanding of the bacterial secretosome, and its action in the maintenance of the cell wall, could suggest ways in which it could be subverted towards the development of new antibiotics. This would generate much needed ammunition in our fight against antimicrobial resistance (AMR).