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Physical characterization of the manganese-sensing pneumococcal surface antigen repressor from Streptococcus

John P Lisher1, Khadine A Higgins, Michael J Maroney

  • 1Department of Chemistry and ‡Interdisciplinary Graduate Program in Biochemistry, Indiana University , Bloomington, Indiana 47405-7102, United States.

Biochemistry
|September 27, 2013
PubMed

Insights

The pneumococcal surface antigen repressor (PsaR) protein binds manganese and zinc in distinct sites, regulating bacterial virulence. Site 2 is crucial for manganese-specific DNA binding activation, essential for pathogenic bacteria survival.

Area of Science:

  • Microbiology and Molecular Biology
  • Bacterial Pathogenesis
  • Protein-Metal Interactions

Background:

  • Transition metals like manganese are vital for pathogenic bacteria, influencing virulence and persistence.
  • In Streptococcus pneumoniae (Spn), manganese homeostasis involves the PsaBCA uptake complex and MntE efflux transporter.
  • PsaR, a metalloregulatory protein, controls the expression of psaBCA, impacting manganese uptake.

Purpose of the Study:

  • To comprehensively analyze the metal and DNA binding properties of the PsaR protein.
  • To elucidate the roles of distinct metal-binding sites in PsaR's regulatory function.
  • To understand the mechanism of PsaR's allosteric activation of DNA operator binding.

Main Methods:

  • Biophysical characterization of PsaR's metal and DNA binding properties.
  • X-ray absorption spectroscopy to determine metal-ligand coordination.
  • Mutational studies to identify critical residues for metal-dependent regulation.

Main Results:

  • PsaR functions as a homodimer, binding two metal ions (Mn(II) or Zn(II)) per protomer at two distinct sites (Site 1 and Site 2).
  • Site 1, likely occupied by Zn(II) in vivo, is necessary but insufficient for full allosteric activation of DNA binding.
  • Site 2 is the primary regulatory site, conferring Mn(II) specificity; Asp7 is critical for Mn(II)-dependent activation of DNA binding.

Conclusions:

  • PsaR's metal-binding sites exhibit differential affinities and roles in regulating gene expression.
  • The study reveals a detailed mechanism for manganese-specific allosteric activation of DNA binding by PsaR.
  • Findings contribute to understanding metalloregulation in DtxR/MntR family proteins and bacterial metal homeostasis.

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