Molecular basis for manganese sequestration by calprotectin and roles in the innate immune response to invading bacterial pathogens

Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):3841-6. doi: 10.1073/pnas.1220341110. Epub 2013 Feb 19.

Abstract

The S100A8/S100A9 heterodimer calprotectin (CP) functions in the host response to pathogens through a mechanism termed "nutritional immunity." CP binds Mn(2+) and Zn(2+) with high affinity and starves bacteria of these essential nutrients. Combining biophysical, structural, and microbiological analysis, we identified the molecular basis of Mn(2+) sequestration. The asymmetry of the CP heterodimer creates a single Mn(2+)-binding site from six histidine residues, which distinguishes CP from all other Mn(2+)-binding proteins. Analysis of CP mutants with altered metal-binding properties revealed that, despite both Mn(2+) and Zn(2+) being essential metals, maximal growth inhibition of multiple bacterial pathogens requires Mn(2+) sequestration. These data establish the importance of Mn(2+) sequestration in defense against infection, explain the broad-spectrum antimicrobial activity of CP relative to other S100 proteins, and clarify the impact of metal depletion on the innate immune response to infection.

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

  • Amino Acid Substitution
  • Binding Sites
  • Calgranulin A / chemistry
  • Calgranulin A / genetics
  • Calgranulin A / immunology
  • Calgranulin B / chemistry
  • Calgranulin B / genetics
  • Calgranulin B / immunology
  • Crystallography, X-Ray
  • Histidine / chemistry
  • Host-Pathogen Interactions / immunology
  • Humans
  • Immunity, Innate*
  • Leukocyte L1 Antigen Complex / chemistry*
  • Leukocyte L1 Antigen Complex / genetics
  • Leukocyte L1 Antigen Complex / immunology*
  • Leukocyte L1 Antigen Complex / pharmacology
  • Manganese / metabolism*
  • Models, Molecular
  • Mutagenesis, Site-Directed
  • Protein Multimerization
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Recombinant Proteins / immunology
  • Recombinant Proteins / pharmacology
  • Staphylococcus aureus / drug effects
  • Staphylococcus aureus / growth & development
  • Staphylococcus aureus / immunology
  • Zinc / metabolism

Substances

  • Calgranulin A
  • Calgranulin B
  • Leukocyte L1 Antigen Complex
  • Recombinant Proteins
  • Manganese
  • Histidine
  • Zinc

Associated data

  • PDB/4GGF