Poster Presentation Australian Society for Microbiology Annual Scientific Meeting 2018

Elucidating the Zn(II)-binding mechanism of the pneumococcal protein AdcAII (#403)

Marina L Zupan 1 , Zhenyao Luo 2 3 4 , Victoria G Pederick 1 , Bostjan Kobe 2 3 4 , James C Paton 1 , Christopher A McDevitt 1
  1. Research Centre for Infectious Diseases, The University of Adelaide, Adelaide, SA, Australia
  2. School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, QLD, Australia
  3. Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, QLD, Australia
  4. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia

Streptococcus pneumoniae (the pneumococcus) is a globally significant human pathogen responsible for 1 – 2 million deaths annually. To colonise and persist within the host, the pneumococcus must acquire the transition metal ion zinc [Zn(II)], present at low concentrations in the host environment. In S. pneumoniae, Zn(II) import is facilitated by the ATP-binding cassette transporter, AdcCB, and two Zn(II)-specific solute binding proteins, AdcA and AdcAII. Although AdcA and AdcAII both deliver Zn(II) to the AdcCB transporter, AdcAII has a more critical role for survival during Zn(II) starvation. Despite the known importance of AdcAII in pneumococcal Zn(II) uptake, the molecular details of how the protein selectively acquires Zn(II) remain poorly understood. To date, our understanding of the Zn(II)-binding mechanism has been based solely on the Zn(II)-bound crystal structure of AdcAII, with an open, metal-free conformation remaining refractory to crystallographic approaches. As a consequence, the conformational changes that occur within AdcAII upon Zn(II)-binding remain unknown. Here, we overcame this issue by mutating each of the four Zn(II)-coordinating residues of AdcAII and performing structural and biochemical analyses on the variant isoforms. Structural analyses of the Zn(II)-bound AdcAII variant isoforms revealed how specific regions within the protein undergo conformational changes via their direct coupling to each of the metal-binding residues. Complementing this work, metal-binding studies revealed that mutagenesis of the coordinating residues altered both the metal ion selectivity of the protein and its affinity for Zn(II). Collectively, these results provide new insight into the mechanism of Zn(II)-binding by AdcAII and the biophysical basis by which the protein confers selectivity for this essential metal ion.