Structural biology of key virulence factors: autotransporter proteins

Bacterial pathogens deploy an arsenal of virulence factors to establish infection and cause disease. At the forefront of the infection process are bacterial surface components, which are responsible for host colonisation and pathogen adhesion. An important group of surface proteins are autotransporter proteins. Autotransporters are the largest group of outer membrane and secreted proteins in bacteria. They are involved in cell adhesion, toxicity and promote the formation of aggregated communities and biofilms, which are critical strategies bacteria use to resist the host immune response and antibiotics. Furthermore, autotransporter proteins are also highly immunogenic and are integral components of human vaccines.

Despite their central role in bacterial pathogenesis and their potential for vaccine development, the three-dimensional structure of most autotransporter proteins has not been characterized and the precise molecular mechanism of how these proteins function is still unknown. Our research focuses on the architecture and mode of action of autotransporter proteins from pathogenic bacteria. We investigate the structural diversity of this family of proteins to identify the features that impart functionality. In this context we have recently elucidated the architecture of Ag43, an autotranporter protein that self associates forming bacterial aggregates and biofilms.

Our studies have shown unprecedented details of how this protein works in the infection process. Identification of the structural determinants underlying autotransporter function will not only define functional epitops but will be the basis for the development of strategies that block their function.