Poster Presentation BacPath 13: Molecular Analysis of Bacterial Pathogens Conference 2015

A unique mechanism of zinc acquisition in Streptococcus pneumoniae (#165)

Jacqueline R. Morey 1 , Zhenyao Luo 2 , Bart A. Eijkelkamp 1 , Charles D. Plumptre 1 , Bostjan Kobe 2 , Rafael Counago 2 , Megan L. O'Mara 3 , James C. Paton 1 , Christopher A. McDevitt 1
  1. Research Centre for Infectious Diseases, University of Adelaide, Adelaide, SA
  2. School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD
  3. Research School of Chemistry, Australian National University, Canberra, ACT

Streptococcus pneumoniae (the pneumococcus) is a significant human pathogen that causes more than 1 million deaths every year. Acquisition of the transition metal zinc from the host environment is essential for pneumococcal colonisation and invasive disease. Pneumococci acquire zinc via the ATP-binding cassette importer AdcCB, which is paired with the zinc-specific substrate-binding protein (SBP) AdcA. Unusually, AdcA consists of two domains: a canonical SBP domain with homology to ZnuA (ZnuA-domain), and a C-terminal domain that has homology to the Gram-negative zinc chaperone ZinT (ZinT-domain). Only the ZnuA-domain directly interacts with AdcCB for zinc transport. AdcA also features a highly mobile histidine-rich loop, the function of which remains unclear. Here we present the in vitro and in vivo characterisation of AdcA. We show that each domain of AdcA can bind one zinc ion, and that the affinities of these zinc-binding sites range from micromolar (ZinT-domain) to nanomolar (ZnuA-domain), suggesting a potential order of zinc interaction. The high-resolution structure of zinc-bound AdcA was then solved to 1.55 Å, and showed that the two domains could potentially interact. This suggests that transfer of zinc between the two domains could occur, from the lower affinity ZinT-domain to the higher affinity ZnuA-domain. We have also analysed zinc acquisition by AdcA in vivo using a zinc-limited mouse model of infection, to probe the role of host zinc during bacterial infection. Collectively, our data suggest that AdcA utilises a unique two-step mechanism for zinc binding, whereby zinc is transferred from the ZinT-domain to the ZnuA-domain, which can then release zinc to AdcCB for transport into the bacterial cell. In the host environment, where free zinc abundance is tightly regulated, this process likely serves to increase the efficiency of zinc acquisition by the pneumococcus, thereby facilitating more effective colonisation and disease in humans.