Sequential assembly of the bacterial flagellum outside the living cell

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Bacteria are the smallest of all cells and live lives of feast and famine. To survive they must sense and adapt quickly to their ever-changing external environment. To find food and escape danger, many bacteria build on their cell surface long rotating propellers called flagella, which allow them to move rapidly over surfaces and through liquids. Motility driven by surface flagella is important to colonization of rich niches in human, animal and plant hosts by disease-causing (pathogenic) bacteria. Both biologists and physicists have long found flagella fascinating as they illustrate beautifully how complex biological structures, comprising a number of discrete substructures, are assembled meticulously from thousands of distinct protein subunit building blocks to operate as tiny rotary 'nanomachines' outside the living cell. They have even been claimed by creationists, who cite their exquisite structural-functional complexity as evidence against slow evolution! Remarkably, the flagellum is fundamentally self-assembling and this feat of nanoscale construction is rendered even more astonishing by the fact that each new subunit building block, made inside the cell, must travel up to 20 times the length of the cell through a narrow central channel in the growing flagellum to incorporate at its tip far outside the cell. Until recently, the mystery was how the subunit building blocks travel through the long channeI where there is no discernable energy source to propel them. We have discovered that this is powered by the subunits themselves, as they link in a chain that is pulled to the flagellum tip. We now propose to use molecular, biochemical and structural biology approaches to build on this completely new and unanticipated chain mechanism for flagellum growth to address a major open question concerning the assembly of the complex flagellum structure: how are the many different subunit building blocks incorporated into the flagellum in the correct sequence? The proposed work has the potential to reveal new aspects of flagellum assembly and provide a deeper understanding of how multi-component biological machines can be assembled beyond the surface of living cells. Findings from this work could, ultimately, be exploited to discover new molecules to block the function of such machines, leading to the development of new drug therapies to treat bacterial infections.