Oral Presentation Lorne Infection and Immunity 2018

The molecular mechanism of how Gram-negative bacteria closely adhere to host surfaces (#4)

Jason Paxman 1 , Alvin Lo 2 , Santosh Panjikar 3 , Mike Kuiper 4 , Chi-Hao Luan 5 , Mark A Schembri 2 , Begoña Heras 1
  1. Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
  2. Australian Infectious Diseases Research Centre, School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
  3. Macromolecular Crystallography, Australian Synchrotron, Clayton, VIC, Australia
  4. Molecular & Materials Modelling group Data61, CSIRO, Docklands, Melbourne, VIC, Australia
  5. High Throughput Analysis Laboratory and Department of Molecular Biosciences, Northwestern University, Chicago, Illinois, U.S.A.

Autotransporter non-fimbrial adhesins are the most widespread and abundant cell surface proteins found throughout Gram-negative bacteria.  These adhesins are 100 fold smaller than the better characterised fimbrial adhesins, and as such are responsible for intimate binding of bacteria to host cell surfaces along with contributing to the formation of bacterial aggregates and biofilms.  Despite their prevalence and importance in bacterial pathogenesis, the structures and mechanisms of action for the vast number of autotransporters is unknown.

 

Recently we elucidated how autotransporter adhesins such as Antigen 43a from uropathogenic E. coli promote bacterial aggregation and biofilm formation1.  The self-association between surface Antigen 43a proteins on neighbouring bacteria causes the cells to clump and form biofilms.

 

However, the mechanism by which most autotransporter adhesins that directly bind to host cell surfaces had remained unknown.  Here we describe the first structure and mode of action for such an adhesin, UpaB from uropathogenic E. coli and uncovered in molecular detail how this adhesin binds to epithelial surfaces.  The UpaB structure was revealed to be a significant departure from the common autotransporter β-helix to accommodate a large groove to interact with host glycosaminoglycans.  Furthermore,  the opposite face of UpaB was found to bind one of the most common targets for bacterial proteins, fibronectin.  Strikingly, unlike most bacterial fibronectin binding proteins, UpaB was found to bind fibronectin type III via a completely new type of interaction. Overall, the two different binding sites on UpaB likely co-operate to allow intimate colonisation of the uroepithelium by uropathogenic E. coli.  Given the multitude of autotransporter adhesins widespread throughout bacteria, the UpaB binding mechanism is likely to be a common mode of interaction utilised for close binding with host cell surfaces.  Apart from shedding new light on bacteria-host interactions, these findings have significant implications for the development of antimicrobials.

  1. 1. Heras B, Totsika M, Peters KM, Paxman JJ, Gee C, Jarrott R, Perugini MA, Whitten AE, 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.