A New Structural Paradigm in Copper Resistance in Streptococcus Pneumoniae

Nat Chem Biol. 2013 Mar;9(3):177-83. doi: 10.1038/nchembio.1168. Epub 2013 Jan 27.

Abstract

Copper resistance has emerged as an important virulence determinant of microbial pathogens. In Streptococcus pneumoniae, copper resistance is mediated by the copper-responsive repressor CopY, CupA and the copper-effluxing P(1B)-type ATPase CopA. We show here that CupA is a previously uncharacterized cell membrane-anchored Cu(I) chaperone and that a Cu(I) binding-competent, membrane-localized CupA is obligatory for copper resistance. The crystal structures of the soluble domain of CupA and the N-terminal metal-binding domain (MBD) of CopA (CopA(MBD)) reveal isostructural cupredoxin-like folds that each harbor a binuclear Cu(I) cluster unprecedented in bacterial copper trafficking. NMR studies reveal unidirectional Cu(I) transfer from the low-affinity site on the soluble domain of CupA to the high-affinity site of CopA(MBD). However, copper binding by CopA(MBD) is not essential for cellular copper resistance, consistent with a primary role of CupA in cytoplasmic Cu(I) sequestration and/or direct delivery to the transmembrane site of CopA for cellular efflux.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Binding Sites
  • Cell Membrane / chemistry
  • Cell Membrane / metabolism
  • Copper / metabolism
  • Copper / pharmacology*
  • Crystallography, X-Ray
  • Drug Resistance, Bacterial* / drug effects
  • Drug Resistance, Bacterial* / genetics
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Mutation / genetics
  • Protein Structure, Tertiary
  • Streptococcus pneumoniae / chemistry*
  • Streptococcus pneumoniae / drug effects
  • Streptococcus pneumoniae / metabolism
  • Streptococcus pneumoniae / pathogenicity

Substances

  • Bacterial Proteins
  • CopA protein, Bacteria
  • Copper

Associated data

  • PDB/4F2E
  • PDB/4F2F