Oral Presentation The 42nd Lorne Conference on Protein Structure and Function 2017

New insights into the structure and mechanism of action for the large family of autotransporter virulence factors (40765)

Jason J Paxman 1 , Alvin Lo 2 , Santosh Panjikar 3 , Mark Schembri 2 , Begoña Heras 1
  1. La Trobe Institute for Molecular Science, Melbourne, VIC, Australia
  2. Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia
  3. Macromolecular Crystallography, Australian Synchrotron, Clayton, VIC, Australia

Autotransporter proteins are the largest group of outer membrane and secreted virulence factors from medically important bacterial pathogens such as Salmonella enterica, Shigella flexneri, Neisseria meningitidis and pathogenic E. coli strains. These long β-solenoid structures can incorporate many different key functions associated with bacterial pathogenesis, acting as adhesins, toxins, mediators of biofilm formation amongst others. With such fundamental roles in bacterial virulence and obvious importance to human health in an era of increasing antibiotic resistance, it is not surprising that they have generated a great deal of interest as targets for therapeutic intervention. However, despite this interest, there are only a dozen structures of autotransporters in the PDB and their mechanisms of action remain largely unknown.

 

Our research centres on the AIDA-I-type autotransporters which are the largest family of autotransporters. We were the first to determine the structure and mechanism of action for one of these family members Antigen 43a from uropathogenic E. coli (UPEC)1. Our work showed that Antigen 43 causes UPEC aggregation and biofilm formation, through forming head-to-tail associations on the bacterial surfaces of neighbouring cells. Aggregation and biofilm formation are critical for UPEC colonisation and persistence within the urinary tract.

 

At present our 2 new autotransporter structures have revealed further unprecedented findings with respect to the structure – function relationships for this family of proteins. We have found an unexpected structural plasticity of the β-helices to incorporate new functions. We have revealed the different strategies employed by these autotransporters to facilitate bacterial colonisation. Our work has also provided structural insights into a new mode of binding for bacterial adhesins. In addition, we have determined how these proteins can switch from different roles in pathogenesis. We have now utilised this information to successfully develop specific inhibitors for key autotransporters.

  1. [1] Heras B, Totsika M, Peters KM, Paxman JJ, Gee CL, Jarrott RJ, Perugini MA, Whitten AE and Schembri MA (2014) The antigen 43 structure reveals a molecular Velcro-like mechanism of autotransporter-mediated bacterial clumping, Proc Natl Acad Sci USA 111, 457-462.